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Multiple Sclerosis: 'There is no individual MS gene'

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Scientists deepen genetic understanding of MS

Genes And MSFive scientists, including two from Simon Fraser University, have discovered that 30 per cent of our likelihood of developing Multiple Sclerosis (MS) can be explained by 475,806 genetic variants in our genome. Genome-wide Association Studies (GWAS) commonly screen these variants, looking for genetic links to diseases.

Corey Watson, a recent SFU doctoral graduate in biology, his thesis supervisor SFU biologist Felix Breden and three scientists in the United Kingdom have just had their findings published online in Scientific Reports. It's a sub-publication of the journal Nature.

An inflammatory disease of the central nervous system, MS is the most common neurological disorder among young adults. Canada has one of the highest MS rates in the world.

Watson and his colleagues recently helped quantify MS genetic susceptibility by taking a closer look at GWAS-identified variants in the major histocompatibility complex (MHC) region in 1,854 MS patients. The region has long been associated with MS susceptibility.

The MS patients' variants were compared to those of 5,164 controls, people without MS. They noted that eight percent of our 30-per-cent genetic susceptibility to MS is linked to small DNA variations on chromosome 6, which have also long been associated with MS susceptibility.

The MHC encodes proteins that facilitate communication between certain cells in the immune system. Outside of the MHC, a good majority of genetic susceptibility can't be nailed down because current studies don't allow for all variants in our genome to be captured.

"Much of the liability is unaccounted for because current research methods don't enable us to fully interrogate our genome in the context of risk for MS or other diseases," says Watson.

The researchers believe that one place to look for additional genetic causes of MS may be in genes that have variants that are rare in the population.

"The importance of rare gene variants in MS has been illustrated in two recent studies," notes Watson, now a postdoctoral researcher at the Mount Sinai School of Medicine in New York.

"But these variants, too, are generally poorly represented by genetic markers captured in GWAS, like the one our study was based on."

Simon Fraser University is Canada's top-ranked comprehensive university and one of the top 50 universities in the world under 50 years old. With campuses in Vancouver, Burnaby and Surrey, B.C., SFU engages actively with the community in its research and teaching, delivers almost 150 programs to more than 30,000 students, and has more than 120,000 alumni in 130 countries.

Source: Medical Xpress © Medical Xpress 2011-2012 (26/10/12)

Gene could be used to treat Multiple Sclerosis

Genes and MSNew treatments for multiple sclerosis (MS) and other auto-immune diseases could flow from an important discovery made by scientists at NUI Maynooth.

They were trying to understand the role of a gene called Pellino3 and how it comes into play when a person develops a viral infection.

They found it acts as a “braking system” that helps to regulate the immune response during infection. Details of the work, led by Paul Moynagh, director of the Institute of Immunology at NUI Maynooth, are published today in the prestigious journal Nature Immunology.

The gene regulates production of proteins called interferons, explained Prof Moynagh. These are released by the body as soon as it detects an invading virus. As their name implies, they interfere with the virus’s ability to replicate and to invade nearby cells.

The release of these powerful proteins must be kept under check however, said Prof Moynagh. “If they are not tightly controlled the person can end up with auto-immune diseases.”

If too many interferons are released it can lead to inflammatory diseases such as lupus, while having too few available during infection can trigger diseases such as multiple sclerosis and support damage caused by other viruses such as hepatitis.

The 10 scientists in his group did intensive research into the role of Pellino3, using a mouse model, and have clarified its function in regulating the production of interferons. “Pellino3 seems to be a key molecule for switching interferons off,” he said.

Prof Moynagh, who is also the new head of the Department of Biology at Maynooth, won a Science Foundation Ireland principal investigator award in support of the research. The Health Research Board also backed the work via the PhD Scholars Programme in Immunology.

The team is now seeking ways to exploit the finding, which has “potential for the treatment of major auto-immune diseases”.

“The ultimate objective of our project is the development, production and commercialisation of pharmaceuticals which can help to combat immune-mediated diseases such as multiple sclerosis.”

The findings were also a clear example of the benefits of supporting basic research. This type of research “feeds the pipeline through which pharmaceutical development and disease treatment can occur”, said Prof Moynagh.

Source: IrishTimes.com © 2012 irishtimes.com (08/10/12)

Transcription profile distinguishes subgroups in MS

MS and GeneticsPatients with multiple sclerosis (MS) can be differentiated according to their transcription profile, according to a study published in the Sept. 26 issue of Science Translational Medicine.

Linda Ottoboni, R.N., from the Brigham and Women's Hospital in Boston, and colleagues examined the structure of an MS patient population using a transcriptional profile generated from peripheral blood mononuclear cells.

Among 141 untreated patients, the researchers identified two subsets of MS patients (MSA and MSB). This structure was replicated in two additional groups of patients with MS, one treated with glatiramer acetate (94 patients) and the second treated with interferon-β (128 patients). Higher expression of molecules involved in lymphocyte signaling pathways was seen in subgroup MSA. In addition, patients in subgroup MSA were significantly more likely to experience a new inflammatory event while on treatment with glatiramer acetate or interferon-β.

"Overall, we report a transcriptional signature that distinguishes a subset of MS patients with more active disease," the authors write. "Stratifying MS subjects into meaningful subsets in this manner has potential for personalizing patient care and for enhancing our understanding of this disease."

Two authors disclosed financial ties to the pharmaceutical industry. Affymetrix Inc. produced the RNA data.

Abstract

The multiple sclerosis (MS) patient population is highly heterogeneous in terms of disease course and treatment response. We used a transcriptional profile generated from peripheral blood mononuclear cells to define the structure of an MS patient population. Two subsets of MS subjects (MSA and MSB) were found among 141 untreated subjects.

We replicated this structure in two additional groups of MS subjects treated with one of the two first-line disease-modifying treatments in MS: glatiramer acetate (GA) (n = 94) and interferon-β (IFN-β) (n = 128). One of the two subsets of subjects (MSA) was distinguished by higher expression of molecules involved in lymphocyte signaling pathways.

Further, subjects in this MSA subset were more likely to have a new inflammatory event while on treatment with either GA or IFN-β (P = 0.0077). We thus report a transcriptional signature that differentiates subjects with MS into two classes with different levels of disease activity.

Full Article

Source: Doctors Lounge Copyright © 2001-2012 Doctors Lounge & Science Copyright © 2012, American Association for the Advancement of Science (27/09/12)

Gene flaw 'explains why drugs failed to treat MS'

MS GeneticsScientists have identified why a once-promising class of drugs do not help people with multiple sclerosis.

An Oxford University team say an genetic variant linked to MS means the drugs which work for patients with other autoimmune diseases will not work for them.

The team, writing in Nature, say the drugs can actually make symptoms worse.

Experts say the work shows how a person's genetic make-up could affect how they responded to treatment.

The drugs, called anti-TNFs, work for patients with rheumatoid arthritis and inflammatory bowel disease, but they have not done so for patients with MS and researchers were unsure why.

Mimicking

The Oxford University team looked at one particular genetic variant, found in a gene called TNFRSF1A, which has previously been associated with the risk of developing MS.

The normal, long version of the protein sits on the surface of cells and binds the TNF signalling molecule, which is important for a number of processes in the body.

But the team discovered the variant caused the production of an altered, shortened version which "mops up" TNF, preventing it from triggering signals - essentially the same thing that TNF blocking drugs do.

In the future, this could help ensure that people with MS are offered drug treatments that are most likely to work for them.

This explains why a study 10 years ago found the drugs make MS patients significantly worse and exacerbate the disease, the researchers suggest.

Professor Lars Fugger of the Nuffield Department of Clinical Neurosciences, who led the work, said: "The hope has been that analyses of the whole human genome would lead to findings that are clinically relevant.

"We show that this is possible. It's one of the first such examples, certainly in autoimmune disease."

He added: "Whilst the TNFRSF1A gene variant is linked to a modest risk of developing MS, the drug that mimics the effect of the variant has a considerably greater impact.

"The effects of genetic variants influencing disease risk or resistance can be amplified by drugs. This has often been completely overlooked, but will be critical for using genetic findings in a medical context."

Nick Rijke, director of policy and research at the MS Society, said: "There are many genes associated with MS, but we know little about the role they play or the influence they have on the condition.

"This important study has shown that some of your genes can play a part in deciding whether or not you respond to a treatment.

"In the future this could help ensure that people with MS are offered the drug treatments that are most likely to work for them."

Source: BBC News © British Broadcasting Corporation 2012 (09/07/12)

Multiple Sclerosis: 'There is no individual MS gene'

MS GeneticsAround 10,000 people in Austria suffer from multiple sclerosis (MS). It is a disease whose exact cause remains unclear. “It is very likely due to a combination of genetic and environmental factors. But there is no individual 'MS gene’”, said Karl Vass from the University Department of Neurology at the MedUni Vienna to mark the occasion of International MS Day on Wednesday.

In two studies which featured considerable involvement of the MedUni Vienna, the role of the MHC gene has now been confirmed in the development of multiple sclerosis, and it has been discovered that the diagnostic procedures used for adults are also effective for children.

Multiple sclerosis in children is rare. Five per cent of all cases of MS start at a very young age. It is usually teenagers who are affected. Says Vass: “This may be due to the development of autoimmunity during puberty.”

In a multicentre study led by Barbara Bajer-Kornek from Karl Vass’s team, 50 young MS patients were investigated at the time their disease first manifested itself. It was found that the diagnostic procedures used for adults, such as MRI scans, cerebrospinal fluid analysis or electrophysiological investigations, also yield good results in young people and that consequently “off-label” drugs - with the doses for adults calculated appropriately for children, since there are usually no studies involving such drugs - are the right way forward, says Vass.

A timely diagnosis generally has a very important role to play in the treatment of multiple sclerosis. Says Vass: “The earlier we are able to establish a diagnosis of MS, the more effectively we are able to respond and draw conclusions regarding the right treatment.” Vienna General Hospital treats around 1,000 patients per year. The prospects for MS patients have improved markedly in recent years. “Anyone given a diagnosis of MS nowadays has much better chances of being able to live their lives with less disability and a better quality of life.”

Vass is confident that new drugs will improve patients’ outlook even further. These are drugs that need to be tested in studies: “Patients involved in a study also get much better care and have a better prognosis,” says the neurologist, who is keen to allay any scepticism about taking part in studies.

On the quest for the ‘MS genes’ a combination of genetic and environmental factors is responsible for the development of multiple sclerosis. A “north/south divide” has also been noted: In Sweden and Scotland, for example, there are twice as many cases of MS as in Austria. Says Vass: “This may have something to do with the sun and the body’s metabolism of vitamin D.

”MS is not inherited, “but if one parent had MS, then the general risk increases from 1:1000 to 1:100,” explains the MedUni researcher. This also confirms that there is no ‘individual’ MS gene responsible for triggering the onset of the disease.

900 Austrian patients with MS were investigated in a second multicentre study carried out in collaboration between the MedUni Vienna, the Medical University of Innsbruck, SMZ-Ost in Vienna and the Medical University of Graz. This study also demonstrated the importance of the MHC gene in the development of the disease. Says Vass: “This gene is only involved in around four per cent of patients, however.” Nevertheless, this finding represents an important step towards identifying the genes that influence the onset of the condition.

More information: Multiple Sclerosis Journal: “Evaluation of the 2010 McDonald multiple sclerosis criteria in children with a clinical isolated syndrome.” B. Kornek, et al. Mult Scler, 23 April 2012. DOI: 10.1177/1352458512444661

Neurogenetics: “Replication study of multiple sclerosis (MS) susceptibility alleles and correlation of DNA-variants with disease features in a cohort of Austrian MS patients.” M. Schmied, et al. Neurogenetics, 2012 May, 13(2);181-187, DOI: 10.1007/s10048-012-0316-y

Source: Medical Xpress © Medical Xpress 2011-2012 (31/05/12)

Brain mapping reveals how genes organize the surface of the brain

Brain MapThe first atlas of the surface of the human brain based upon genetic information has been produced by a national team of scientists, led by researchers at the University of California, San Diego School of Medicine and the VA San Diego Healthcare System. The work is published in the journal Science.

The atlas reveals that the cerebral cortex - the sheet of neural tissue enveloping the brain - is roughly divided into genetic divisions that differ from other brain maps based on physiology or function. The genetic atlas provides scientists with a new tool for studying and explaining how the brain works, particularly the involvement of genes.

"Genetics are important to understanding all kinds of biological phenomena," said William S. Kremen, PhD, professor of psychiatry at the UC San Diego School of Medicine and co-senior author with Anders M. Dale, PhD, professor of radiology, neurosciences, and psychiatry, also at the UC San Diego School of Medicine.

According to Chi-Hua Chen, PhD, first author and a postdoctoral fellow in the UC San Diego Department of Psychiatry, "If we can understand the genetic underpinnings of the brain, we can get a better idea of how it develops and works, information we can then use to ultimately improve treatments for diseases and disorders."

The human cerebral cortex, characterized by distinctive twisting folds and fissures called sulci, is just 0.08 to 0.16 inches thick, but contains multiple layers of interconnected neurons with key roles in memory, attention, language, cognition and consciousness.

Other atlases have mapped the brain by cytoarchitecture - differences in tissues or function. The new map is based entirely upon genetic information derived from magnetic resonance imaging (MRI) of 406 adult twins participating in the Vietnam Era Twin Registry (VETSA), an ongoing longitudinal study of cognitive aging supported in part by grants from the National Institutes of Health (NIH). It follows a related study published last year by Kremen, Dale and colleagues that affirmed the human cortical regionalization is similar to and consistent with patterns found in other mammals, evidence of a common conservation mechanism in evolution.

"We are excited by the development of this new atlas, which we hope will help us understand aging-related changes in brain structure and cognitive function now occurring in the VETSA participants," said Jonathan W. King, PhD, of the National Institute on Aging, part of the NIH.

The atlas plots genetic correlations between different points on the cortical surface of the twins' brains. The correlations represent shared genetic influences and reveal that genetic brain divisions do not map one-to-one with traditional brain divisions that are based on structure and function. "Yet, the pattern of this genetic map still suggests that it is neuroanatomically meaningful," said Kremen.

Kremen said the genetic brain atlas may be especially useful for scientists who employ genome-wide association studies, a relatively new tool that looks for common genetic variants in people that may be associated with a particular trait, condition or disease.

Source: Medical News Today © MediLexicon International Ltd 2004-2012 (02/04/12)

Clues to causes of nerve cell degeneration provided by spasticity gene finding

Genetics and MSThe discovery of a gene that causes a form of hereditary spastic paraplegia (HSP) may provide scientists with an important insight into what causes axons, the stems of our nerve cells, to degenerate in conditions such as multiple sclerosis.

In the Journal of Clinical Investigation, an international team of scientists led by Dr Evan Reid at the University of Cambridge, and Dr Stephan Zuchner from the University of Miami, report that mutations in the gene known as 'reticulon 2' on chromosome 19 cause a form of HSP, a condition characterised by progressive stiffness and contraction (spasticity) of the legs, caused by selective and specific degeneration of axons

The team identified three mutations in the reticulon 2 gene as causing a type of HSP - in one case, this mutation included an entire deletion of the gene. In addition, the researchers showed that reticulon 2 interacts with another gene, spastin. Mutations in this latter gene cause the most common form of hereditary spastic paraplegia.

Reticulon 2 provides the genetic code for a reticulon protein that is a member of a family of proteins recently shown to play a key role in shaping the endoplasmic reticulum. The endoplasmic reticulum is a network of interconnected sheets and tubules that extends throughout the cytoplasm in nearly all cells. It has a number of functions, including protein synthesis, calcium signalling and regulation of other components of the cell. Recent data suggest that the sheets are involved in protein synthesis, whereas the tubules are specialised to carry out the other functions.

This new study provides the most direct evidence to date that defects in how the endoplasmic reticulum is shaped and formed could underlie axon degeneration. When axons degenerate, signals are unable to pass through the nerve cells, leading to a breakdown of communication within the central nervous system. This is common in degenerative diseases of the nervous system, such as multiple sclerosis.

"Our work highlights important new disease mechanisms, which may provide a platform for us to study how axons are damaged in devastating illnesses such as HSP, and perhaps even in multiple sclerosis, which in some cases is very similar to HSP," explains Dr Reid, a Wellcome Trust Senior Research Fellow in Clinical Science. "But we must not forget how this work may immediately directly benefit families affected by hereditary spastic paraplegia, for whom the discovery now opens up the possibility of genetic counselling and testing."

Source: Medical News Today © MediLexicon International Ltd 2004-2012 (11/01/12)

Three novel Multiple Sclerosis susceptibility loci identified

MS and GeneticsThree novel multiple sclerosis (MS) genetic susceptibility loci have been identified, according to a meta-analysis published in the December issue of the Annals of Neurology.

Nikolaos A. Patsopoulos, M.D., Ph.D., from the Brigham and Women's Hospital in Boston, and colleagues investigated MS susceptibility and explored the functional consequences of novel susceptibility loci.

They performed a one-stage meta-analysis of seven genome-wide association studies involving 2,529,394 unique single nucleotide polymorphisms obtained from 5,545 patients with MS and 12,153 controls. Quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 individuals with demyelinating disease were used to explore RNA expression data.

The researchers identified three novel susceptibility alleles: rs170934T on chromosome 3p24.1 (odds ratio [OR], 1.17), rs2150702G on chromosome 9p24.1 (OR, 1.16), and rs6718520A on chromosome 2p21 (OR, 1.17). There was no strong cis effect on RNA expression in PMBCs associated with these loci. Suggestive associations were seen in 10 additional loci.

"These results extend the list of loci associated with MS from earlier genome scans and confirm theoretical predictions that increasing sample sizes will lead to additional discoveries given the magnitude of effect seen for non-major histocompatibility complex MS susceptibility loci," the authors write.

Several authors disclosed financial ties to the pharmaceutical industry.

Full Article

Source: The Doctor's Lounge Copyright © 2001-2012 Doctors Lounge (09/01/12)

Rare gene links vitamin D and multiple sclerosis

MS And GeneticsA rare genetic variant which causes reduced levels of vitamin D appears to be directly linked to multiple sclerosis, says an Oxford University study.

UK and Canadian scientists identified the mutated gene in 35 parents of a child with MS and, in each case, the child inherited it.

Researchers say this adds weight to suggestions of a link between vitamin D deficiency and MS.

The study is in Annals of Neurology.

Multiple sclerosis is an inflammatory disease of the central nervous system (the brain and spinal cord).

Although the cause of MS is not yet conclusively known, both genetic and environmental factors and their interactions are known to be important.

Oxford University researchers, along with Canadian colleagues at the University of Ottawa, University of British Columbia and McGill University, set out to look for rare genetic changes that could explain strong clustering of MS cases in some families in an existing Canadian study.

They sequenced all the gene-coding regions in the genomes of 43 individuals selected from families with four or more members with MS.

The team compared the DNA changes they found against existing databases, and identified a change in the gene CYP27B1 as being important.

When people inherit two copies of this gene they develop a genetic form of rickets - a disease caused by vitamin D deficiency.

Just one copy of the mutated CYP27B1 gene affects a key enzyme which leads people with it to have lower levels of vitamin D.

Overwhelming odds
The researchers then looked for the rare gene variant in over 3,000 families of unaffected parents with a child with MS.

They found 35 parents who carried one copy of this variant along with one normal copy.

In every one of these 35 cases, the child with MS had inherited the mutated version of the gene.

The likelihood of this gene's transmission being unconnected to the MS is billions to one against, say the researchers.

Prof George Ebers, lead study author at Oxford University, says the odds are overwhelming.

"All 35 children inheriting the variant is like flipping a coin 35 times and getting 35 heads, entailing odds of 32 billion to one against."

He added: "This type of finding has not been seen in any complex disease. The uniform transmission of a variant to offspring with MS is without precedent but there will have been interaction with other factors."

Prof Ebers believes that this new evidence adds to previous observational studies which have suggested that sunshine levels around the globe - the body needs sunshine to generate vitamin D - are linked to MS.

He maintained that there was now enough evidence to carry out large-scale studies of vitamin D supplements for preventing multiple sclerosis.

"It would be important particularly in countries like Scotland and the rest of the UK where sunshine levels are low for large parts of the year. Scotland has the greatest incidence of multiple sclerosis of any country in the world."

Dr Doug Brown, head of biomedical research at the MS Society, called it an important development.

"This shines more light on the potential role of vitamin D deficiency on increasing the risk of developing MS.

"This research is gathering momentum and will be the subject of discussion at an international expert meeting in the USA this month, the outcomes of which will shape future research that will give us the answers we so desperately need about the potential risks and benefit of vitamin D supplementation."

Paul Comer, from the charity MS Trust, said the research strengthened the case for vitamin D being one potential contributory cause of MS.

"Current opinion suggests that a combination of genetic predisposition, environmental factors such as exposure to sunlight and possibly some sort of trigger, such as a viral infection, interact in some way to start the development of MS.

"We welcome any research that clarifies the interplay between these factors. This is another step towards finding ways to reduce the risk of developing MS, but it is likely to be some years yet before we can gauge the significance of vitamin D deficiency to MS."

Source: BBC News © British Broadcasting Corporation 2011 (09/12/11)

HLA-DRB1*15:01 and multiple sclerosis: a female association?

MS And GeneticsAbstract

Background: The association between multiple sclerosis (MS) and the HLA-DRB1*15:01 haplotype has been proven to be strong, but its molecular basis remains unclear. Vitamin D receptor (VDR) gene variants and sex have been proposed to modulate this association.

Objectives: 1) Test the association of MS with *15:01 and VDR variants; 2) check whether VDR variants and/or sex modulate the risk conferred by *15:01; 3) study whether *15:01, VDR variants and/or sex affect HLA II gene expression.

Methods: Peripheral blood from 364 MS patients and 513 healthy controls was obtained and DNA and total RNA were extracted from leukocytes. HLA-DRB1, DRB5 and DQA1 gene expression measurements and *15:01 genotyping were performed by qPCR. VDR variants were genotyped by PCR-RFLP.

Results: Our data confirms that the *15:01 haplotype confers a higher risk of suffering from MS (OR = 1.364; 95% CI = 1.107–1.681). No association was found between VDR variants and MS, but they were shown to moderately modulate the risk conferred by *15:01. Sex confers a much stronger modulation and the *15:01-MS association seems to be female specific. A higher *15:01 frequency has been observed in Basques (45.1%). *15:01 positive samples showed a significant overexpression of DRB1 (p < 0.001), DRB5 (p < 0.001) and DQA1 (p = 0.004) in patients. DRB1 (p = 0.004) and DRB5 (p < 0.001) were also overexpressed in *15:01 controls.

Conclusions: We confirm the *15:01-MS association and support that it is female specific. The relevance of ethnic origin on association studies has also been highlighted. HLA-DRB1*15:01 seems to be a haplotype consistently linked to high HLA II gene expression.

Full Article

Haritz Irizar, Maider Muñoz-Culla, Olaia Zuriarran, Estibaliz Goyenechea, Tamara Castillo-Triviño, Alvaro Prada, Matias Saenz-Cuesta, Dolores De Juan, Adolfo Lopez de Munain, Javier Olascoaga, David Otaegui


Source: Sage Journals Online © 2011 by SAGE Publications (30/11/11)

Genetic clues to what triggers Multiple Sclerosis

MS And GeneticsAround 30 genetic risk factors for developing multiple sclerosis have been discovered by a UK-led team.

It brings to more than 50 the total number of genetic clues to the disease.

The research, published in Nature, will help identify risk factors and perhaps future treatments or even a cure, said the MS Society.

Most of the genes are linked to immunity, backing the idea that the disease is triggered when the immune system turns against itself.

Genes are only part of the story, however, with other factors, such as vitamin D or a viral infection, thought to play an important role.

The study, carried out by a consortium of international researchers, led by the universities of Oxford and Cambridge, is the largest yet into genes and MS.

It looked at DNA from almost 10,000 MS patients, and more than 15,000 healthy controls.

Twenty three known genetic variations, common in the general population, that give a tiny increase in the risk of getting MS were confirmed, and 29 new ones identified.

Another five are strongly suspected as being involved, bringing the total number of genetic variations associated with MS to 57.

Professor Alistair Compston of the University of Cambridge told the BBC: "This is suddenly a big new number of genes to try to understand.

"80% of the genes that are implicated by the 57 'hits' are immunological. This shouts out that this is an immunological disease at the beginning. This is a very important confirmation."

Around 2.5 million people around the world have MS, 100,000 of them in the UK.

MS is not directly inherited and there is no single gene that causes it. However, research suggests a combination of genes common in the general population make some people more susceptible to developing the neurological disorder.

Other environmental factors are involved, possibly something in the environment, such as a virus or bacteria, or Vitamin D from exposure to sunlight.

Simon Gillespie, Chief Executive of the MS Society said: "By identifying which genes may trigger the development of MS, we can identify potential 'risk factors' and look at new ways of treating, or even preventing, the condition in the future."

Some of the genes found to be important in MS are also implicated in other autoimmune disorders, such as Crohn's disease and Type 1 diabetes, a separate research paper, published in PLoS Genetics, has reported.

Source: BBC News © British Broadcasting Corporation 2011 (11/08/11)

Genome-wide association study of severity in multiple sclerosis

Genetics And MSSummary: A study conducted by the International Multiple Sclerosis Genetics Consortium studied 1470 MS cases and performed a genome-wide association study of more than 2.5 million single-nucleotide polymorphisms to identify loci influencing disease severity, measured using the MS severity score.

No single result achieved genome-wide significance. Interestingly, the authors also report that variants within previously confirmed MS susceptibility loci do not appear to influence severity. The authors therefore conclude that disease severity is likely to be polygenic and comprised of modest effects, similar to what has been described for MS susceptibility to date.

Abstract
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component.

Several lines of evidence support a strong role for genetic factors influencing both disease susceptibility and clinical outcome in MS.

Identification of genetic variants that distinguish particular disease subgroups and/or predict a severe clinical outcome is critical to further our understanding of disease mechanisms and guide development of effective therapeutic approaches.

We studied 1470 MS cases and performed a genome-wide association study of more than 2.5 million single-nucleotide polymorphisms to identify loci influencing disease severity, measured using the MS severity score (MSSS), a measure of clinical disability.

Of note, no single result achieved genome-wide significance. Furthermore, variants within previously confirmed MS susceptibility loci do not appear to influence severity.

Although bioinformatic analyses highlight certain pathways that are over-represented in our results, we conclude that the genetic architecture of disease severity is likely polygenic and comprised of modest effects, similar to what has been described for MS susceptibility, to date. However, a role for major effects of rare variants cannot be excluded. Importantly, our results also show the MSSS, when considered as a binary or continuous phenotype variable is by comparison a stable outcome.

International Multiple Sclerosis Genetics Consortium, Briggs FB, Shao X, Goldstein BA, Oksenberg JR, Barcellos LF, De Jager PL.

Source: Genes Immun. 2011 Jun 9. doi: 10.1038/gene.2011.34. and Pubmed PMID: 21654844 (22/06/11)

Rogue enzyme implicated in Multiple Sclerosis

MS GeneticsGenetic analysis of a Canadian family with an extraordinarily high prevalence of multiple sclerosis suggested that a rogue tyrosine kinase may play a role in causing the disease, a researcher said here.

A rare variant in the gene for a Janus-associated kinase called TYK2 was found in four members of this family, fitting well into current theories of the disease, according to Sreeram Ramagopalan, MD, of the University of Oxford in England.

That genetic factors play a role in MS is not in doubt, but most of the genetic players remain shadowy.

One region related to human leukocyte antigen (HLA) molecules is believed to be the main genetic locus in MS, Ramagopalan explained during a platform presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers. But studies have indicated that it explains only about half of the apparent heritability in MS.

Searches for other common genetic variants to account for the remaining half have mostly come up empty, suggesting that rare variants must be responsible.

He said TYK2 is one of the first rare genetic variants to be identified firmly in connection with a complex disease such as MS.

Some 86% of family members with MS versus 42% of unaffected members carried the TYK2 variant isolated in the study, Ramagopalan told CMSC attendees.

A confirmatory genotype analysis in another group of 2,104 MS cases and 894 healthy controls showed that the variant was more common in cases with an odds ratio of 3.7 (P=1.6 x 10-7), he said.

There were also functional reasons to find the relationship plausible, Ramagopalan said.

“It has a crucial role in signal transduction for a wide range of cytokines, including type 1 interferons, IL-10, and IL-12,” he said.

He also noted that TYK2 deficiency had previously been shown to produce immunodeficiency with reduced Th1 and increased Th2 cytokines, and that a different variant in TYK2 was associated with reduced risk of MS in a patients-versus-controls study.

All of which suggested that perhaps the variant identified in the Canadian family represents a gain-of-function mutation in the enzyme.

Intriguingly, Ramagopalan also indicated that TYK2 may also interact with vitamin D-related pathways. Inadequate vitamin D levels have recently been linked to increased MS incidence, although whether there is a causal connection remains uncertain.

Other studies have found that vitamin D helps regulate the balance between Th1 and Th2 immune responses. The former is associated with MS and other autoimmune conditions whereas Th2 is benign.

Conceivably, he said, the TYK2 variant seen in this family may make carriers less responsive to vitamin D, or more responsive to its insufficiency, leading to an exaggerated Th1 profile relative to most people.

On the other hand, he said only MS was over-represented in the family, not other autoimmune diseases that are also linked to Th1 responses.

This family is already well known in MS research. It was first identified in 1991; by 2002, 14 of 45 members across three generations were diagnosed with the disease and two others were thought to be possibly affected.

For the new study, Ramagopalan and colleagues sequenced the entire exome (the portion of the genome coding directly for proteins) of four randomly selected MS patients in this family. Polymorphisms, insertions, and deletions relative to standard sequences were catalogued.

About 20,000 SNPs and 1,840 insertions and deletions were common to all four. Filtering to highlight those most likely to be damaging shrank the number to 768.

But when a linkage analysis was performed, only one shook out: the TYK2 variant.

Of course, an actual causal relationship, and the degree to which it may apply outside this family, remains to be determined, Ramagopalan said

The study was funded by the Multiple Sclerosis Society of Canada and the Multiple Sclerosis Society of Great Britain and Northern Ireland.
Ramagopalan and colleagues declared they had no relevant financial interests.

Source: MedPage Today © 2011 Everyday Health, Inc. (08/06/11)

Link between environment and genetics in triggering MS found

MS And GeneticsEnvironmental and inherited risk factors associated with multiple sclerosis – previously poorly understood and not known to be connected – converge to alter a critical cellular function linked to the chronic neurologic disease, researchers with the UC Irvine Multiple Sclerosis Research Center have discovered.

The findings, which appear in the online, open-access journal Nature Communications, suggest that a unifying mechanism may be responsible for multiple sclerosis and point to therapies personalized according to genetic factors.

"MS results from complex interactions between an individual's genetics and his or her environment," said study leader Dr. Michael Demetriou, a UCI neurologist and associate director of the Multiple Sclerosis Research Center. "Defining how these come together to induce the disease is critical for developing a cure. We've taken a giant first step toward understanding this."

Using blood samples from about 13,000 people, Demetriou and colleagues identified the way environmental factors – including metabolism and vitamin D3, obtained through either sunlight exposure or diet – interact with four genes (interleukin-7 receptor-alpha, interleukin-2 receptor-alpha, MGAT1 and CTLA-4) to affect how specific sugars are added to proteins regulating the disease.

Earlier work on mice by Demetriou revealed that changes in the addition of these specific sugars to proteins engender a spontaneous MS-like disease. They also found that N-acetylglucosamine (GlcNAc), a dietary supplement and simple sugar related to glucosamine, is able to suppress this process.

The current research shows that both vitamin D3 and GlcNAc can reverse the effects of four human MS genetic factors and restore the normal addition of sugars to proteins. "This suggests that oral vitamin D3 and GlcNAc may serve as the first therapy for MS that directly targets an underlying defect promoting disease," Demetriou said.

Virtually all proteins on the surface of cells, including immune and nervous system cells, are modified with complex sugars of variable lengths and composition. This adds information to proteins separate from that directly defined by the genome. The sugars interact with specific sugar-binding proteins on the cell, forming a molecular lattice that controls the clustering, signaling and surface expression of critical receptors and transporters, such as the T cell receptor and CTLA-4. Reducing sugar modification weakens the lattice and enhances growth and activity of immune system T cells in such a way that they increase neural degeneration – a hallmark of MS.

Production of the complex sugars is regulated by both metabolic and enzymatic functions, the latter altered by genetic MS risk factors and vitamin D3. Demetriou pointed out that the MGAT1 genetic variant linked to MS increases or decreases the sugars attached to proteins depending on metabolism – one possible explanation for why people with the same genetic risk factor may or may not develop MS.

These sugars have also been implicated in many other chronic diseases, such as diabetes and cancer, Demetriou added, so this work could open up entirely new areas of medicine.

Source: Eureka Alert! (01/06/11)

New molecular mechanism for MS identified

MS And GeneticsGenetic defects in inflammatory responses or the so-called braking signals that lead to an overactivation of the immune system may predispose the brain to multiple sclerosis, say researchers.

"We demonstrate that there is a new molecular pathogenic mechanism that underlies the initiation and progression of multiple sclerosis," report investigators led by Francesca Gilli, PhD, from the University Hospital San Luigi Gonzaga in Torino, Italy.

The work was published online March 14 in the Archives of Neurology.

The authors recently published another genome-wide transcriptional analysis in which they identified a gene signature for multiple sclerosis that reverted back to normal during pregnancy (PLoS One. 2010;5:e8962). Reversion was particularly evident for 7 genes: SOCS2, TNFAIP3, NR4A2, CXCR4, POLR2J, FAM49B, and STAG3L1. Most of these have already been linked to inflammation.

In this new comparison study, Dr. Gilli and her team wanted to confirm the dysregulation of genes, evaluate the prognostic value, and study gene modulation during different treatments.

They performed quantitative polymerase chain reaction measurements for 274 patients with multiple sclerosis and 60 healthy controls.

Of the patients with multiple sclerosis, 113 were treatment-naive in the initial stages of disease and were followed in real-world clinical settings. The remaining 161 patients with multiple sclerosis received disease-modifying therapies for a mean of 12 months. About one third received interferon beta (Avonex, Biogen Idec), another third were treated with glatiramer acetate (Copaxone, Sanofi-Aventis), and another third received natalizumab (Tysabri, Biogen Idec).

The main outcome measures were gene expression levels, relapse rate, and change in Expanded Disability Status Scale score.

Genes Correlate With Clinical Features

"We found a dysregulated gene pathway," report the researchers, citing a P value of .006 or less. There was a downregulation of genes encoding negative regulators. The SOCS2, NR4A2, and TNFAIP3 genes were inversely correlated with both relapse rate (P ≤ .002) and change in Expanded Disability Status Scale score (P ≤ .005).

"The results of our study show that altered gene expression correlates with clinical features," the researchers note. "Our findings indicate a correlation between reduced expression of SOCS2, NR4A2, and TNFAIP3 and a worse disease course."

Previous studies have shown a consistent association between autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis, and 4 genes: CXCR4, SOCS2, NR4A2, and TNFAIP3.

"These genes have been proposed to be critical 'braking' molecules acting to control inflammation in autoimmunity," the authors explain. They suggest that multiple sclerosis arises from a dysregulation of braking signals in inflammation rather than from an overactive proinflammatory reaction.

The investigators found that SOCS2 was modulated by both interferon beta and glatiramer acetate. TNFAIP3 was modulated by glatiramer acetate, and NR4A2 was not altered at all. In patients treated with natalizumab, 1 of 7 genes — FAM49B — reverted its expression to normal (P < .001).

"Our findings clearly show that there are partial differential overlapping mechanisms of protection between disease-modifying therapy and pregnancy because each of the drugs leads to the reversion in expression of some, but not all, of the pregnancy-related genes," they note.

All this information, the researchers say, can be used to design powerful new diagnostic tools and identify new therapeutic targets.

This study was funded by the Italian Multiple Sclerosis Foundation. It was also supported by the Ricerca Biomedica Foundation and the San Luigi Gonzaga Organization. Dr. Francesca Gilli and colleagues have received funding for travel and lectures from Merck-Serono, Sanofi-Aventis, Biogen, Novartis Bayer Schering, and Teva.

Source: Nedscape Today Copyright © 1994-2011 by WebMD LLC (18/03/11)

Gene analysis illuminates MS therapy side effect

MS and GeneticsLeukemia that was observed in a small number of mitoxantrone treated multiple sclerosis patients may be the result of patients' genetic makeup, Italian researchers said.

Variations in genes involved with DNA repair processes and in the gene encoding the CYP3A4 drug-metabolizing enzyme were significantly associated with secondary acute promyelocytic leukemia (sAPL) in a case-control study, according to Francesco Lo-Coco, MD, of Tor Vergata University in Rome, and colleagues online in Neurology.

Specific single nucleotide polymorphisms (SNPs) in the BRCA1 and BRCA2 genes and in the gene for CYP3A4 were more common in mitoxantrone-treated patients who developed sAPL and also predicted faster onset of the condition, the researchers found.

Variants in another DNA-repair gene known as XRCC5 also were associated with sAPL in the study.

The findings may help to explain why some MS patients develop sAPL after taking mitoxantrone while others do not.

"Combinations of allelic variants in different pathways may have even greater impact on secondary leukemia risk than single gene alterations," Lo-Coco and colleagues wrote.

"In keeping with this view, we found that carriers of both variant alleles of XRCC5 and BRCA2 had a 50-fold increased risk of sAPL, suggesting that this synergistic effect of variation results in significantly hampered DNA repair capacity."

The study was prompted by observations that sAPL appeared to be very common among MS patients receiving mitoxantrone. One 2009 report linking MS and leukemia put the rate at 7.4 per 1,000 patients treated.

Primarily a DNA-damaging cancer drug, mitoxantrone was approved 10 years ago for MS treatment, but many neurologists have regarded it as a treatment of last resort because of the sAPL risk.

The new study raises the possibility of identifying patients at lower risk for sAPL, which could lead to a revival of interest in mitoxantrone.

Lo-Coco and colleagues performed genotype analyses in 18 MS patients who developed sAPL after taking mitoxantrone, two MS patients diagnosed with sAPL after taking other drugs, 41 mitoxantrone-treated MS patients who did not develop sAPL, 253 MS patients who neither took mitoxantrone nor developed sAPL, and 310 healthy blood donors.

From five to nine years of follow-up was available for most patients.

Among the 18 patients with sAPL after mitoxantrone treatment, the median duration of treatment when sAPL was diagnosed was 26.5 months.

The genotyping scanned for 210 SNPs in 22 DNA-repair and drug-metabolizing enzyme genes. One SNP each in the BRCA1, BRCA2, XRCC5, and CYP3A4 genes appeared to drive much of the risk for sAPL.

All mitoxantrone-treated patients who were homozygous for the risk alleles of BRCA2 and XRCC5 developed sAPL within three years (P<0.05), and all such patients with two copies of the risk-associated BRCA1 SNP had been diagnosed with sAPL within about six years (P=0.015).

In contrast, not even half of patients with other genotypes had developed sAPL by the end of follow-up.

Associations involving CYP3A4 variants were different. Patients homozygous for an adenine base at the target location were less likely to develop sAPL, whereas the riskiest genotype was heterozygosity for adenine and guanine (P=0.01) with about 20% of patients with the genotype remaining free of the leukemia at final data analysis.

"Our data, although obtained in a limited number of sAPL series arising after MS and of [mitoxantrone]-treated patients with MS who did not develop sAPL, point to increased sAPL susceptibility for patients harboring certain genetic variants of DNA repair and drug-metabolizing enzymes," Lo-Coco and colleagues wrote.

"Confirmation of our findings in larger series and functional in vitro studies are warranted to confirm that these genetic variants are linked to leukemogenesis in patients with MS."

Source: Medpage Today (c) 2011 Everyday Health, Inc (28/02/11)

Modeling the cumulative genetic risk for MS from genome wide association data

MS and GeneticsMultiple Sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance.

Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed.

Methods: We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples).

Analysis of Covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degree of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool.

Results: In the discovery dataset, the median cumulativegenetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, together with 79.9% classification sensitivity and 95.8% specificity.

The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, with classification sensitivity 62.3%, and the specificity 75.9%.

No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (High, Medium, Low, Misclassified). On the other hand, a significant difference (F=2.75, p=0.04) was detected for age of disease onset between the affected misclassified as controls (mean=36 yrs.) and the other three groups (High: 33.5 yrs.; Medium: 33.4 yrs.; Low: 33.1 yrs.).

Conclusion: The results are consistent with the polygenic model of inheritance.

The cumulative genetic risk established using currently available genome-wide association data provides important insights into disease heterogeneity and completeness of current knowledge in MS genetics.

Authors: Joanne Wang Derek Pappas Philip De Jager Daniel Pelletier Paul de Bakker Ludwig Kappos Chris Polman Australian and New Zealand Multiple Sclerosis Genetics Consortium Lori Chibnik David Hafler Paul Matthews Stephen Hauser Sergio Baranzini Jorge Oksenberg

Source: 7thspace.com © 2011 7thSpace Interactive (19/01/11)

Women with MS more likely to have MS-related gene than men

Genetics & MSWomen who have multiple sclerosis (MS) are more likely to have a gene associated with multiple sclerosis than men with the disease and it is this gene region where environment interacts with the genetics, according to a study published in the January 5, 2011, online issue of Neurology®, the medical journal of the American Academy of Neurology.

Research has shown that the number of people diagnosed with MS has been rising, and the rate has been rising faster for women than for men.

The cause of MS is not known, but evidence suggests that it is triggered by environmental factors in people who are genetically susceptible to the disease. The main gene associated with MS is the human leukocyte antigen (HLA) class II gene, but most of the risk comes from interaction of both parental genes.

The study examined the HLA genes of 1,055 families with more than one person with MS in the family. The genes of 7,093 people were tested, which included 2,127 people with MS. The researchers looked at what the HLA genes were for the people with and without MS, whether people with MS inherited the susceptibility gene from their mother or their father, and what the relationship was between people in the same family with MS.

The researchers found that women with MS were 1.4 times more likely to have the HLA gene variant associated with MS than men with MS. A total of 919 women and 302 men had the HLA gene variant, compared to 626 women and 280 men who did not have the gene variant. This fits with other research by this research group showing that the environment interacts with this gene region to produce modification in risk associated with it. This appears to be an epigenetic mechanism.

"Our findings also show women with the HLA gene variant are more likely to transmit the gene variant to other women in their families than to men," said study author George C. Ebers, MD, FMedSCi, of the University of Oxford in the United Kingdom and a member of the American Academy of Neurology.

The researchers also determined that second-degree relatives such as aunts and their nieces or nephews were more likely to inherit the gene variant than first-degree relatives such as siblings or parents and children.

"It appears that the less the genetic sharing between individuals, the higher the interaction is between female sex and inheritance of the HLA gene variant," said Orhun Kantarci, MD, of the Mayo Clinic in Rochester, Minn., and a member of the American Academy of Neurology, who wrote an editorial on the study. "These findings pave the way for future studies of these genes, hopefully to advance our understanding of inheritance of complex diseases such as MS."

Source: Eureka Alert! (06/01/11)

Experiment brings hope for new multiple sclerosis treatment

MS and GeneticsJapanese and Swiss researchers have shed light on what causes multiple sclerosis (MS) symptoms to worsen, and succeeded in developing a medicine that alleviates MS symptoms in mice.

The researchers expect their findings to assist in the development of new medications for the disease.

MS causes inflammation in the spinal cord and nerves in the brain such as the optic nerve. The symptoms include impaired vision and difficulty walking. In Japan, there are over 12,000 people with the disease, and around 80 percent of them are only in their 20s to 40s. If symptoms worsen, patients can end up blind or bed-ridden. The cause of MS is unknown, and most treatment is limited to fighting symptoms -- using steroids that reduce inflammation or drugs that suppress the immune system.

The symptoms of MS occur when the myelin sheaths that cover the optic nerve and axons in the spinal cord are damaged by inflammation, causing the electric signals that transmit information through the nervous system to leak and not be transmitted effectively.

Dr. Takayuki Harada and Dr. Xiaoli Guo from the Tokyo Metropolitan Institute for Neuroscience and others involved with the research set their sights on ASK1. ASK1 is a gene that works in glial cells, which support the cranial nerves, and controls the innate immune system that organisms are born with. The researchers theorized that on appearance of MS symptoms, ASK1 is overly activated, leading to the secretion of large amounts of protein that cause inflammation.

When the researchers artificially induced MS-like symptoms in mice that had their ASK1 genes removed, the symptoms, such as lower-body paralysis, did not worsen and the mice were able to continue walking. The myelin sheaths around the mice's axons were barely damaged.

The researchers also developed a drug that impedes the activity of ASK1. After administering the drug daily to the mice with MS-like symptoms, the mice's conditions improved.

The ASK1 gene exists in humans as well. "If a new medicine like the ASK1 inhibitor can be developed for humans, it will become easy to inhibit inflammation of the central nerves," says Harada.

The research was published in the European Molecular Biology Organization's scientific journal, the EMBO Journal.

Source: Copyright 2011 THE MAINICHI NEWSPAPERS (04/01/11)

The genetic basis of multiple sclerosis:a model for MS susceptibility MS & GeneticsMS-pathogenesis is known to involve both multiple environmental events, and several independent genetic risk-factors.

Methods: A model of susceptibility is developed and a mathematical analysis undertaken to elucidate the nature of genetic susceptibility to MS and to understand the constraints that are placed on the genetic basis of MS, both by the known epidemiological facts of this disease and by the known frequency of the HLA DRB1*1501 allele in the general populations of northern Europe and North America.

Results: For the large majority of cases (possibly all), MS develops, in part, because an individual is genetically susceptible. Nevertheless, 2.2% or less of the general population is genetically susceptible.

Moreover, from the model, the number of susceptibility-loci that need to be in a "susceptible allelic state"to produce MS-susceptibility is small (11-18), whereas the total number of such susceptibility-loci is large (50-200), and their "frequency of susceptibility"is low (i.e ., [less than or equal to] 0.12). The optimal solution to the model equations (which occurs when 80% of the loci are recessive) predicts the epidemiological data quite closely.

Conclusions: The model suggests that combinations of only a small number of genetic loci in a "susceptible allelic state"produce MS-susceptibility.

Nevertheless, genome-wide associations studies with hundreds of thousands of SNPs, are plagued by both false-positive and false-negative identifications and, consequently, emphasis has been rightly placed on the replicability of findings. Nevertheless, because genome-wide screens don't distinguish between true susceptibility-loci and disease-modifying-loci, and because only true susceptibility-loci are constrained by the model, unraveling the two will not be possible using this approach.The model also suggests that HLA DRB1 may not be as uniquely important for MS-susceptibility as currently believed.

Thus, this allele is only one among a hundred or more loci involved in MS susceptibility. Even though the "frequency of susceptibility"at the HLA DRB1 locus is four-fold that of other loci, the penetrance of those susceptible genotypes that include this allele is no different from those that don't.

Also, almost 50% of genetically-susceptible individuals, lack this allele. Moreover, of those who have it, only a small fraction ([less than or equal to] 5.2%) are even susceptible to getting MS.

Author: Douglas Goodin
Credits/Source: BMC Neurology 2010, 10:101

Source: 7th Space Interactive © 2010 7thSpace Interactive (29/10/10)

Chance discovery may be MS research breakthrough

Genes and MSAn accidental discovery in a University of Alberta lab could lead to new treatments for multiple sclerosis.

“That,” said Marak Michalak, one of the two biochemists who made the discovery that led to the breakthrough, “is the beauty of open minded, curiosity-driven research.”

Michalak and Allison Kraus were doing genetic research unrelated to MS five years ago when they stumbled upon a link between a specific gene in nerve cells and myelin, the insulation coating the cells.

They were studying how certain genes function, and found when they removed a certain protein, they accidentally created neurological diseases.

Whenever the protein, known as calnexin, was removed they found the myelin coating the cells became weaker and loose, just like MS.

Michalak compared it to insulation around an electrical wire — if the wire isn’t properly protected, the electricity leaks out, reducing the cell’s ability to transmit.

The lab models — rats — had difficulty moving, displaying symptoms similar to MS and other neurological diseases.

“Myelin diseases are so diverse and so tricky to figure out,” he said. “Nobody understands why these diseases happen which cause people to progressively lose their motor functions. We have discovered a new player in myelin diseases that was never considered before. It’s been an interesting and unexpected discovery.”

When they realized what they had found, a team of researchers was assembled around the world to study it further. Their findings were recently published in the Journal of Biological Chemistry.

Neil Pierce, president of the local MS society chapter, which helped fund the study, called it “a big day for Albertans. My hope is that another new treatment is in the offing. For someone with MS, this could have a major impact on their life.”

Source: Edmonton Sun Copywrite 2010 Edmonton Sun (17/09/10)

Gene variant may increase severity of MS

MS GeneticsA new study shows a gene variant may increase the severity of multiple sclerosis (MS) symptoms. The research will be published in the August 3, 2010, issue of Neurology®, the medical journal of the American Academy of Neurology.

For the study, researchers screened the oligoadenylate synthetase (OAS1) gene in 401 people with MS, 394 people without MS and 178 people receiving the MS treatment beta interferon.

On the analysis of the OAS1 gene, 63 percent of people with MS had the AA genotype compared to 57 percent of people without MS. The GG genotype was found in 37 percent of people with MS compared to 43 percent of people without the disease.

While the OAS1 gene was weakly associated with disease susceptibility, the study found that people who had the AA genotype had earlier relapses and increased disease activity compared to those without the genotype. “While we don’t understand why some patients vary so widely in their disease activity, this genetic association may give us clues to help direct future research,” said study author Margaret O’Brien, PhD, with St. Vincent’s University Hospital in Dublin, Ireland.

The study also found people who had the GG genotype had less disease activity and fewer relapses. “It’s possible that the GG genotype may protect against increased disease activity in people with MS, but more research is needed,” said O’Brien.

The study was supported by Science Foundation Ireland, the Health Research Board of Ireland and MS Ireland.

Source: American Academy of Neurology © 2010 American Academy of Neurology (02/08/10)

Autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer MS susceptibility

MS GeneticsAbstract
Genome-wide association studies (GWAS) have revealed that different diseases share susceptibility variants.

Twelve single-nucleotide polymorphisms (SNPs) previously associated with different immune-mediated diseases in GWAS were genotyped in a Caucasian Spanish population of 2864 multiple sclerosis (MS) patients and 2930 controls.

Three SNPs were found to be associated with MS: rs1678542 in KIF5A (P=0.001, odds ratio (OR)=1.13, 95% confidence interval (CI)=1.05-1.23); rs3184504 in SH2B3 (P=0.00001, OR=1.19, 95% CI=1.10-1.27) and rs763361 in CD226 (P=0.00007, OR=1.16, 95%CI=1.08-1.25). These variants have previously been associated with rheumatoid arthritis and type 1 diabetes.

The SH2B3 polymorphism has additionally been associated with systemic lupus erythematosus.

Our results, in addition to validating some of these loci as risk factors for MS, are consistent with shared genetic mechanisms underlying different immune-mediated diseases.

These data may help to shape the contribution of each pathway to different disorders.

Genes and Immunity advance online publication, 27 May 2010; doi:10.1038/gene.2010.30.

Alcina A, Vandenbroeck K, Otaegui D, Saiz A, Gonzalez JR, Fernandez O, Cavanillas ML, Cénit MC, Arroyo R, Alloza I, García-Barcina M, Antigüedad A, Leyva L, Izquierdo G, Lucas M, Fedetz M, Pinto-Medel MJ, Olascoaga J, Blanco Y, Comabella M, Montalban X, Urcelay E, Matesanz F.

Instituto de Parasitología y Biomedicina 'López Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.

Source: Genes Immun. 2010 May 27 - Pubmed PMID: 20508602 (02/06/10)

MS Gene Expression Regulated By Vitamin D MS Genetics

Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB1*1501 Is Regulated by Vitamin D

Abstract Top
Multiple sclerosis (MS) is a complex trait in which allelic variation in the MHC class II region exerts the single strongest effect on genetic risk.

Epidemiological data in MS provide strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of this disease.

Growing evidence implicates sunlight or vitamin D as a key environmental factor in aetiology.

We hypothesised that this environmental candidate might interact with inherited factors and sought responsive regulatory elements in the MHC class II region.

Sequence analysis localised a single MHC vitamin D response element (VDRE) to the promoter region of HLA-DRB1. Sequencing of this promoter in greater than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes. In contrast, there was striking variation among non–MS-associated haplotypes.

Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15. Transient transfection using a luciferase reporter assay showed a functional role for this VDRE. B cells transiently transfected with the HLA-DRB1*15 gene promoter showed increased expression on stimulation with 1,25-dihydroxyvitamin D3 (P = 0.002) that was lost both on deletion of the VDRE or with the homologous “VDRE” sequence found in non–MS-associated HLA-DRB1 haplotypes. Flow cytometric analysis showed a specific increase in the cell surface expression of HLA-DRB1 upon addition of vitamin D only in HLA-DRB1*15 bearing lymphoblastoid cells.

This study further implicates vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility. These findings support a connection between the main epidemiological and genetic features of this disease with major practical implications for studies of disease mechanism and prevention.

Author Summary Top
Multiple Sclerosis (MS) is a complex neurological disease with a strong genetic component. The Major Histocompatibility Complex (MHC) on chromosome 6 exerts the strongest genetic effect on disease risk. A region at or near the HLA-DRB1 locus in the MHC influences the risk of MS. HLA-DRB1 has over 400 different alleles. The dominant haplotype of Northern Europe, marked by the presence of DRB1*1501, increases risk of MS by 3-fold. The environment also plays a key role in MS. The most striking illustration of this is the geographical distribution of the disease in populations matched for ethnicity. This has led to the proposal that sunshine, and in particular, vitamin D, is an environmental factor influencing the risk of MS. Circumstantial evidence supporting this comes from studies showing the involvement of vitamin D in immune and nervous system function. The current investigation sought to uncover any relationship between vitamin D and HLA-DRB1. It was found that vitamin D specifically interacts with HLA-DRB1*1501 to influence its expression. This study therefore provides more direct support for the already strong epidemiological evidence implicating sunlight and vitamin D in the determination of MS risk, and implies that vitamin D supplementation at critical time periods may be key to disease prevention.

Sreeram V. Ramagopalan 1,2#, Narelle J. Maugeri1#, Lahiru Handunnetthi1,2, Matthew R. Lincoln1,2, Sarah-Michelle Orton1,2, David A. Dyment1,2, Gabriele C. DeLuca1,2, Blanca M. Herrera1,2, Michael J. Chao1,2, A. Dessa Sadovnick3,4, George C. Ebers1,2*, Julian C. Knight1*

1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, 2 Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom, 3 Department of Medical Genetics, Division of Neurology, University of British Columbia, UBC Hospital, Vancouver, British Columbia, Canada, 4 Faculty of Medicine, Division of Neurology, University of British Columbia, UBC Hospital, Vancouver, British Columbia, Canada

Source: Public Library of Science Genetics (20/05/10)

Sardinian study finds genetic variants tied to Multiple Sclerosis

MS GeneticsVariants of a gene called CBLB are associated with multiple sclerosis in humans, a new study finds.

Previous research found that variants of CBLB, which is normally responsible for moderating immune response, influenced MS risk in mice.

In this new study, an international research team analyzed the genomes of MS patients on the Italian island of Sardinia, which has a high incidence of MS and other autoimmune diseases in which the immune system attacks healthy cells.

The study is published in the May 9 issue of Nature Genetics.

Along with the finding about the association between CBLB gene variants and MS, the researchers also confirmed that six genes previously identified as being associated with MS risk in other populations also contribute to the risk of the disease in Sardinians.

People on Sardinia are often used for gene-association studies because of their relative genetic similarity. The initial group of people that settled there more than 8,000 years ago has grown to the modern population of 1.5 million, with few people moving to the island in the interim.

Source: HealthDay © 2010 HealthDay (10/05/10)

MS study suggests key role of environmental factor in the disease

Genes & MSScientists are reporting what they say is compelling evidence that some powerful non-heritable, environmental factor likely plays a key role in the development of multiple sclerosis.

Their finding, the cover article in the April 29, 2010 issue of Nature, results from the most advanced genomic analysis ever conducted on identical, or "monozygote," twins where one sibling has multiple sclerosis and the other does not.

"Even with the very high resolution at which we sequenced the genomes of our study participants, we did not find evidence for genetic, or epigenetic differences that explained why one sibling developed the disease and the other did not," says the lead author of the study, Sergio Baranzini, PhD, associate adjunct professor of neurology and a member of the Multiple Sclerosis Research Group at University of California, San Francisco.

The finding does not mean that genes do not play a role in the disease. In cases where one identical twin has MS, there is a 30-percent increased risk that the identical sibling also will develop the disease. In cases where a non-identical twin or other sibling has the disease, there is an increased risk of nearly 5 percent. However, says Baranzini, while limitations of current technology or small study size may have caused the team to miss important genetic divergence between twins, they consider the findings significant.

The study was the first to examine all three levels of a human genome at the same time, giving the first full picture of a living genome. The scientists examined the genome sequences of one MS-discordant identical twin pair and the messenger RNA transcriptome and epigenome sequences of CD4+ lympohoctyes from three MS-discordant identical twin pairs.

As a probe of a human genome, the study was a tour de force. The MS genome was explored at a depth of 20-fold coverage. By comparison, the first two single human genomes ever published - those of biologist and entrepreneur Craig Venter, PhD, followed by Nobel laureate James Watson, PhD - were sequenced at a depth of 7 to 8 fold coverage. In addition, the study investigated the first female genomes, the first genomes of twins and the first autoimmune disease individual genome sequences.

Source: Physorg.com © PhysOrg.com 2003-2010 (28/04/10)

Genome-wide association study in a high-risk isolate for Multiple Sclerosis reveals associated variants in STAT3 gene

MS GeneticsGenetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles.

Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk.

To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS.

The top 27 loci with p < 10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations.

SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases.

This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.

Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Jakkula E, Leppä V, Sulonen AM, Varilo T, Kallio S, Kemppinen A, Purcell S, Koivisto K, Tienari P, Sumelahti ML, Elovaara I, Pirttilä T, Reunanen M, Aromaa A, Oturai AB, Søndergaard HB, Harbo HF, Mero IL, Gabriel SB, Mirel DB, Hauser SL, Kappos L, Polman C, De Jager PL, Hafler DA, Daly MJ, Palotie A, Saarela J, Peltonen L.

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00290, Finland; Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki 00271, Finland; Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Source: Pubmed PMID: 20159113 (24/02/10)

Multiple sclerosis risk changes with the season

MS and Genetics
Previous studies have shown multiple sclerosis (MS) patients are more often born in spring than in any other season, indicating that there is an environmental risk factor for the disease. A paper in the journal Neurology, reviewed for f1000 Medicine by Emmanuelle Waubant and Ellen Mowry, now suggests that this seasonal effect is mediated by the gene HLA-DRB1.

In many European populations, the HLA-DRB1*15 allele of this gene is associated with an increased risk of MS, and the large-scale study of MS patients from Canada, Sweden and Norway now shows that this allele is more common among patients born in the spring.

Waubant and Mowry said the study was "unique in its attempt to understand how genes and environment interact in MS". However, even though there is a correlation between birth month, genetics and risk of MS, it is not yet clear how this is regulated.

One likely contender is vitamin D, which influences expression of the HLA-DRB1*15 allele. Since vitamin D production fluctuates with the seasons, a vitamin D deficit in pregnant mothers could be related to the increased risk of MS among spring births, but this requires further investigation.

Waubant and Mowry said the study may influence preventative and therapeutic treatments through the understanding of environmental risks and their interaction with relevant genotypes.

Previous studies by the Neurology paper's authors showed that in people who carry the gene variant, a lack of vitamin D during early life might impair the ability of the thymus to delete rogue T cells, which then go on to attack the body, leading to a loss of myelin on the nerve fibres.

Study author Dr Sreeram Ramagopalan said that taking vitamin D supplements during pregnancy may reduce the risk of a child developing MS in later life. Government guidelines also recommend that children under five take daily vitamin D supplements.

Source: EurekaAlert! (29/01/10)

Novel mouse model of demyelinating disorder

MouseIn the February 1st issue of G&D, Dr. Brian Popko (The University of Chicago) and colleagues describe how mutation of a gene called ZFP191 leads to disordered CNS myelination in mice -- reminiscent of what is seen in human multiple sclerosis (MS) patients.

MS is a chronic autoimmune disorder, in which the body attacks and destroys the

Genetic variant associated with Multiple Sclerosis risk may also be linked to number of spinal cord lesions

Spinal XrayMultiple sclerosis (MS) afflicts the central nervous system, causing unpredictable and varying

'I thought I was alone with my MS'

Shiv Sharma
When Shiv Sharma was Vitamin D deficiency (the sun is an important source for vitamin D) and the Epstein-Barr virus, which may increase the risk of developing MS.

"While genes in European and migrant European populations have been studied extensively, South Asian MS has received very little attention," he said.

"The 'speculation' is that in Caucasians genes contribute approximately 40% to risk of MS and that 60% is environmental.

"We assume that South Asians may have an 'intrinsically' higher genetic risk but this is not exposed until the environmental factor is available."

He added that exposure to certain environmental factors in the early years of life - up to the age of 12 - were likely to play a particularly important role in determining risk.

Dr Doug Brown, research manager at the MS Society, said: "We are hoping that this study, which is part of the MS Society's innovative grant award scheme, will give researchers a better idea of how genes might play a role in MS susceptibility, with the eventual goal of opening up new avenues of research into the subject."

Changes needed

Mr Sharma, 44, volunteers for the MS Society, trying to increase awareness among his community about the condition.

He said there urgently needed to be a sea-change in attitudes.

"I know from my work that MS in our community can be shunned and hidden," he said.

"They don't understand it or know the implications of it.

"If you come out and say you have MS they are happy to give you their old remedies but if they have a family member with it they do not disclose it at all.

"They wrap a curtain round the outside world and do not tell anyone.

"I have met people who have been diagnosed with MS at a younger age than myself and who were still living with their parents when they were diagnosed.

"The parent's reaction is not: 'How well are they, or what is it?' but: 'How am I going to get my son or daughter married now?'"

Mr Sharma said there was a tendency to believe that MS brought shame on the community.

"They believe they have either done something wrong in a current or previous life," he said.

"They feel that it is going to affect the marriage issue because women are more likely to get MS than men.

"And they wrongly worry that are going to pass on to their children. There is a lot of ignorance, misinformation and fairy tales."

Source: BBC News © British Broadcasting Corporation 2009 (01/11/09)

Mayo Clinic identifies 2 genes as potential therapeutic targets for multiple sclerosis

MS GeneticsEarly research holds promise for new therapies and better prediction of patient outcomes.

A Mayo Clinic study has found that two genes in mice were associated with good central nervous system repair in multiple sclerosis (MS). These findings give researchers new hope for developing more effective therapies for patients with MS and for predicting MS patients' outcomes. This study will be presented at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis in Dusseldorf, Germany, today, Sept. 11, 2009.

"Most MS genetic studies have looked at disease susceptibility -- or why some people get MS and others do not," says Allan Bieber, Ph.D., a Mayo Clinic neuroscientist and author of this study. "This study asked, among those who have MS, why do some do well with the disease while others do poorly, and what might be the genetic determinants of this difference in outcome."

Mayo Clinic provides care for nearly 2,500 patients with MS each year. MS is a disease of the central nervous system that includes the brain, spinal cord and nerves. MS is called a demyelinating disease because it results from damage to vision, balance and

Association between protective and deleterious HLA alleles with Multiple Sclerosis in central East Sardinia

MS Genetics

The human leukocyte antigen (HLA) complex on chromosome 6p21 has been unambiguously associated with multiple sclerosis (MS).

The complex features of the HLA region, especially its high genic content, extreme polymorphism, and extensive linkage disequilibrium, has prevented to resolve the nature of HLA association in MS.

We performed a family based association study on the isolated population of the Nuoro province (Sardinia) to clarify the role of HLA genes in MS.

The main stage of our study involved an analysis of the ancestral haplotypes A2Cw7B58DR2DQ1 and A30Cw5B18DR3DQ2.

On the basis of a multiplicative model, the effect of the first haplotype is protective with an odds ratio (OR) = 0.27 (95% confidence interval CI 0.13–0.57), while that of the second is deleterious, OR 1.78 (95% CI 1.26–2.50).

We found both class I (A, Cw, B) and class II (DR, DQ) loci to have an effect on MS susceptibility, but we saw that they act independently from each other.

We also performed an exploratory analysis on a set of 796 SNPs in the same HLA region. Our study supports the claim that Class I and Class II loci act independently on MS susceptibility and this has a biological explanation.

Also, the analysis of SNPs suggests that there are other HLA genes involved in MS, but replication is needed. This opens up new perspective on the study of MS.

Roberta Pastorino1*, Cristina Menni1,2, Monserrata Barca3, Luisa Foco1, Valeria Saddi4, Giovanna Gazzaniga3, Raffaela Ferrai4, Luca Mascaretti5, Frank Dudbridge6, Carlo Berzuini6,7, Salvatore Bruno Murgia4, Maria Luisa Piras4, Anna Ticca4, Pier Paolo Bitti3, Luisa Bernardinelli1,6,7

1 Dipartimento di Scienze Sanitarie Applicate e Psicocomportamentali, Università di Pavia, Pavia, Italy, 2 Dipartimento di Statistica, Università di Milano Bicocca, Milano, Italy, 3 Centro di Tipizzazione Tissutale, S.I.T., Presidio Ospedaliero S. Francesco, ASL N°3, Nuoro, Italy, 4 Divisione di Neurologia, Presidio Ospedaliero S. Francesco, ASL N°3, Nuoro, Italy, 5 Blood Transfusion Centre, San Gerardo Hospital, Monza, Italy, 6 MRC Biostatistics Unit, Institute of Public Health, University Forvie Site, Cambridge, United Kingdom, 7 Department of Pure Mathematics and Mathematical Statistics, University of Cambridge, Cambridge, United Kingdom

Source: Elites TV © 2009 KBC Media (06/08/09)

Prediction of acute multiple sclerosis relapses by transcription levels of peripheral blood cells

MS Genetics

The ability to predict the spatial frequency of relapses in multiple sclerosis (MS) would enable physicians to decide when to intervene more aggressively and to plan clinical trials more accurately.

Methods: In the current study our objective was to determine if subsets of genes can predict the time to the next acute relapse in patients with MS. Data-mining and predictive modeling tools were utilized to analyze a gene-expression dataset of 94 non-treated patients; 62 patients with definite MS and 32 patients with clinically isolated syndrome (CIS).

The dataset included the expression levels of 10,594 genes and annotated sequences corresponding to 22,215 gene-transcripts that appear in the microarray.

Results: We designed a two stage predictor. The first stage predictor was based on the expression level of 10 genes, and predicted the time to next relapse with a resolution of 500 days (error rate 0.079, p<0.001).

If the predicted relapse was to occur in less than 500 days, a second stage predictor based on an additional different set of 9 genes was used to give a more accurate estimation of the time till the next relapse (in resolution of 50 days). The error rate of the second stage predictor was 2.3 fold lower than the error rate of random predictions (error rate = 0.35, p<0.001).

The predictors were further evaluated and found effective both for untreated MS patients and for MS patients that subsequently received immunomodulatory treatments after the initial testing (the error rate of the first level predictor was <0.18 with p<0.001 for all the patient groups).

Conclusions: We conclude that gene expression analysis is a valuable tool that can be used in clinical practice to predict future MS disease activity. Similar approach can be also useful for dealing with other autoimmune diseases that characterized by relapsing-remitting nature.

Author: Michael GurevichTamir TullerUdi RubinsteinRotem Or-BachAnat Achiron

Source: BMC Medical Genomics 2009, 2:46 (27/07/09)

In pursuit of a happiness gene

image

The pursuit of happiness characterises the human condition. But for those suffering from stress, money trouble or chronic illness, a positive outlook on life can be difficult to find. Now, a Tel Aviv University researcher says we should look to our genes.

Prof. Yoram Barak of Tel Aviv University's Sackler School of Medicine is engaged in the "attempt to find the happiness gene, the genetic component of happiness," which may be 50% responsible for an optimistic outlook. The research is a collaboration between Tel Aviv University and its affiliated research hospital, the Chaim Sheba Medical Centre at Tel Hashomer, which is the largest hospital in Israel.

Initial research findings have made Prof. Barak optimistic about their ability to succeed. "If something is genetic, it should have a large concordance among twins," he says. "And the twin studies we are looking at show that 50% of happiness is genetically determined." Prof. Barak is now working with Prof. Anat Achiron of the Sheba Medical Center to identify the specific genes that are associated with happiness.

Dr. Barak's current findings in the hunt for the happiness gene were presented at The World Congress on Treatment and Research in Multiple Sclerosis in Montreal, Canada in 2008, and most recently detailed in the journal Expert Review of Neurotherapeutics, April 2009.

Positive psychology

We may be a long way off from being able to genetically engineer happiness, Prof. Barak says, but we can start by thinking positively. Much of his work is based on positive psychology, which is the "fastest and largest growing area of psychology in the United States ― and in the world," he says.

For the 50% of happiness that is not genetic, Prof. Barak is working on a program of positive psychology workshops, with exercises he recently tested in a one-day workshop for 120 participants at the Multiple Sclerosis Society of Israel. Early results indicate that the workshops improved the happiness level of participants by as much as 30%.

This work is dedicated to finding "practical and intervention oriented research and the application of psychology into medicine," says Prof. Barak. His research into the physical affects of mental state on patients with neurological diseases is an attempt to bridge the gap between psychology and clinical medicine.

Feeling good in mind and body

Prof. Barak says that the psychological benefits of the program were accompanied by physical benefits as well. "We were able to raise levels of happiness in these patients so they were just about equal to those of healthy subjects," he says. "If we can apply positive psychology, we can better their adherence to their treatment regime. And we have been able to show that there is a stabilisation of the neurological disability as well."

For healthy individuals, Prof. Barak says that his happiness exercises can enrich their lives, too. Meanwhile, his search for the happiness gene goes on.

Source: Physorg.com © PhysOrg.com 2003-2009 (24/06/09)

Parent of origin effect in multiple sclerosis

MS Genetics

Background: Multiple sclerosis (MS) is a complex neurologic disease with a striking geographical distribution. In Canada, prevalence is high in Caucasians of Northern European ancestry and uncommon in North American Aboriginals, many of whom now have Caucasian admixture.

Methods: The population-based Canadian Collaborative Project on the Genetic Susceptibility to MS provided the characteristics of 58 individuals with 1 Caucasian and 1 North American Aboriginal parent from a database of 30,000 MS index cases.

Results: We found that MS index cases with a Caucasian mother and a North American Aboriginal father had a higher sib recurrence risk and greater F:M sex ratio (p = 0.043) than patients with a North American Aboriginal mother and Caucasian father.

Conclusions: Maternal parent-of-origin effects in multiple sclerosis disease etiology previously seen in studies of half-siblings and avuncular pairs are also seen in Caucasian-North American Aboriginal admixture matings and warrant further investigation. A differential influence of maternal risk transmission on the sex ratio of affected offspring is implied. The method of analysis used may have broader implications for detection of parent-of-origin effects in admixture cohorts.

S. V. Ramagopalan DPhil, I. M. Yee MSc, D. A. Dyment MD, DPhil, S.-M. Orton DPhil, R. A. Marrie MD, PhD, FRCPC, A. D. Sadovnick PhD, G. C. Ebers MD, FRCP, FRCPC, FMedSci*, For the Canadian Collaborative Study Group

From the Wellcome Trust Centre for Human Genetics (S.V.R., D.A.D., S.-M.O., G.C.E.), University of Oxford, Headington; Department of Clinical Neurology (S.V.R., D.A.D., S.-M.O., G.C.E.), University of Oxford, John Radcliffe Hospital, Oxford, UK; Department of Medical Genetics (I.M.Y.) and Faculty of Medicine (A.D.S.), Division of Neurology, University of British Columbia, VCHA-UBC Hospital, Vancouver; and University of Manitoba Health Sciences Centre (R.A.M.), Winnipeg, Canada.

Source: Neurology © 2009 by AAN Enterprises, Inc. (18/06/09)

Researchers piece together more of the MS genetic code

MS and Genetics


Australian and New Zealand scientists are a step closer to unravelling what causes multiple sclerosis.

The researchers have pinpointed two regions in the human genome which contain genes that increase a person's risk of developing the debilitating autoimmune disease.

The scientists say this may lead, eventually to being able to prevent people developing MS.

Commenting on the study, Helen Yates, Multiple Sclerosis Resource Centre Chief Executive said, “This research marks a milestone in the genetic understanding of MS.  To have identified two parts of the human genome that show they have a role to play in the susceptibility of MS is a big step in the right direction for potential interventions in the disease’s development.”

It's a mystery why multiple sclerosis strikes healthy people when they're aged around 30, attacking the nervous system and leading to a range of disabilities including blindness and paralysis.

Scientists know genetics play a part but it's extraordinarily complex.

After scanning the DNA of more than 5,000 people, researchers from Australia and New Zealand have now identified two regions in the human genome which contain genes which increase a person's risk of developing the disease.

The research was coordinated by Dr Justin Rubio from the Howard Florey Institute in Melbourne.

"The increased risk for each gene is about 20 per cent. It seems though that together if you carry both of these genes that you are probably maybe 150 per cent more likely to get MS.", said Dr Rubio

But just because a person has those genes, doesn't necessarily mean they will develop MS.

Other factors, like viruses or environmental influences, are believed to play a part.

For a while scientists have observed that people with a vitamin D deficiency are more prone to developing MS.

Dr Justin Rubio says the new research reinforces that link

"What we've identified is a gene that's involved in vitamin D metabolism, and this we know is important in immune regulation.

So what this is saying is that something in vitamin D metabolism is important. We obviously need to do further work on this to clarify exactly how this might be occurring, but this is, if you like, an important link between genetics and the environment."

Dr Rubio says the study also casts more light on the way genes interact to start causing a person's white blood cells to begin attacking the outer coating of myelin that protects the nerves.

"For one of these genes that we've identified, one of these gene regions, provides a link between immune cells and non-immune cells. It is involved in how they talk to each other, if you like, and how they might then stimulate an immune response.

And there are ways in which this interaction can be modified.

So there's the potential development of treatments to interfere with that process."

But scientists will proceed with caution.

Professor Trevor Kilpatrick from Melbourne University also steered the research.

He says that the two regions the scientists identified are also regions of susceptibility other autoimmune diseases, like Type 1 diabetes and thyroid disease.

"What we found is that the genetic variations which predispose to MS are protective, for example, for Graves' disease and vice versa.

So when we start thinking about new generation therapeutic interventions, we'll have to be very careful about making sure that we're not inducing side effects in terms of inducing susceptibility to other autoimmune diseases."

Nevertheless, today's findings have been welcomed by organisations representing the 20,000 Australians with MS.

Jeremy Wright from MS Research Australia says now that more genes have been identified, scientists will be able to work out the mechanisms involved in the development of the MS

"It's not that each gene might multiply the chances. It's really the code's been unlocked and the chance of identifying how to test for susceptibility is now obviously close. The genes also lead to knowledge about how we can identify new therapies also."

Jeremy Wright says even though those tests or treatments may still be several years away, today's news is still an important step forward.

Source: The World Today © 2009 ABC (15/06/09)

Twin studies and the heritability of Multiple Sclerosis

Twins and MS

Objective
The classical twin study has the potential to evaluate the relative contribution of genes and environment and guide further research strategies, provided the sampling and methods of analysis are correct. We wish to review all the more informative twin studies on multiple sclerosis (MS).

Methods
We examined six large population-based twin studies in MS and calculated indices of heritability (h(2)), which is the traditional method of assessing genetic contribution to disease and to allow comparison between studies.

Results
This index was found to vary widely from 0.25 to 0.76 with large confidence intervals that reflect small sample size and prevent robust interpretation.

Conclusion
Overall the studies support a genetic contribution to disease; however, the imprecision of the heritability estimates and potential biases that they contain mean that very little inference can be drawn its exact size. Given that the magnitude of genetic effect cannot be measured because of the relative infrequency of MS; the consequent difficulty in collecting an informative sample; and in many countries, the lack of a comprehensive twin register, we suggest that further twin prevalence surveys should not be undertaken. Twin studies could be used more effectively in other ways, such as the co-twin case-control approach.

Hawkes Ch, Macgregor A.
Queen Mary University London, Neuroscience Centre, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK

Source: Pubmed PMID: 19482860 (10/06/09)

Final appeal for help with multiple sclerosis study in Scottish islands

Scottish Flag

Scientists conducting a major study into multiple sclerosis in Shetland and Orkney are making a final appeal for volunteers to help them complete their work.

Study leader Jim Wilson, who is based at Edinburgh University, said there had been a “great” response both from those with the disease and those without, but he and his team required some more participants in the latter category.

In particular, they would like females aged between 39 and 51 with one parent from Shetland and one parent from Scotland; females aged between 51 and 63 with one parent from the South Mainland and one parent from the West Mainland; males aged between 60 and 72 with one parent from Scotland and one parent from Shetland; females aged between 47 and 59 with one parent from Shetland and one parent from Scotland; and females aged between 34 and 46 with one parent from Shetland and one parent from Scotland.

The study is attempting to find out why Shetland and Orkney have the highest prevalence of MS in the world. Dr Wilson hopes to find a new gene which influences the risk of developing the disease.

A new MS susceptibility gene was recently discovered in the isolated population of Ostrobothnia in Finland using the exact same approach as is being taken in the Northern Isles. It is unlikely to be the same gene in Finland and Shetland.

He said: “The basis of the study is to compare the DNA of the patients with that of the controls to see if it is possible to identify a gene that differs between them. To do this correctly the controls have to match the cases in terms of sex, age and where their family originates – the North Isles, part of the Mainland, etc.

“In spite of large numbers coming forward as controls, there are still a few patients for whom we do not have a good match and I would like to ask anyone who matches the criteria above but does not have MS among their immediate family to volunteer.

“Being a control involves one visit by Elizabeth Visser, our clinical research fellow, who will provide information about the study, go through a questionnaire to exclude symptoms of MS and then take a small blood sample to allow us to analyse the DNA.”

In addition, Dr Wilson is hoping that more people in their early 70s who are now unlikely to develop the disease will come forward to help.

In particular, the team is looking for females with one parent from the South Mainland and one from England; females with one parent from the Central Mainland and one from Scotland; females with one parent from the Central Mainland and one from Orkney; females with one parent from Bressay and one parent from Scotland; females with one parent from the Central Mainland and one from the North Mainland; females with one parent from the Central Mainland and one from Caithness/Sutherland; males with two parents from Yell; and males with one parent from Scotland and one from the Central Mainland.

Dr Wilson said the study was drawing to a close in the summer so this was the last chance to volunteer and help understand the causes of this devastating disease, and perhaps thereby open up a new avenue for treatment.

He said: “Only by understanding what has gone wrong can we begin to do something about it. Finding the genes is the first step on the road to new drugs against a disease.”

Any MS patients who have not yet volunteered and would like to take part are also welcome to come forward. To volunteer call 0131 651 1643 or email '); document.write(addy53089); document.write('<\/a>'); //-->\n This email address is being protected from spambots. You need JavaScript enabled to view it. " href="mailto: This email address is being protected from spambots. You need JavaScript enabled to view it. "> This email address is being protected from spambots. You need JavaScript enabled to view it.

Source: The Shetland Times © 1996–2008 The Shetland Times (04/06/09)

Genetic hope for Multiple Sclerosis and cancer patients

Genetics and MS

Scots scientists have discovered genetic "brakes" which could slow down or stop diseases such as multiple sclerosis and cancer, it was announced yesterday.

In what has been hailed as a "big step" towards answering one of medical science's great questions, the findings of researchers at the Roslin Institute could lead to new treatments and even cures for illnesses which affect the immune system.

It was previously thought that a select group of "master" genes was responsible for controlling the growth of cells that can cause the conditions.

But the study discovered that there are actually hundreds of genes which interact with each other in a way that is much more complicated than previously thought.

MS, a disease in which the immune system mistakenly attacks and damages the myelin sheath that protect nerve cells, can cause symptoms ranging from vague tingling to blindness and paralysis. It affects one in every 500 people in Scotland – the highest proportion in the world – and nearly 100,000 across the UK.

Professor David Hume, the director of the University of Edinburgh's Roslin Institute, said a whole new field of scientific research had been opened up, which would dramatically alter the way in which vaccines were used and drugs were tested.

MS charities last night welcomed the findings which, they said, highlighted Scotland's leading role in research into the illness, while cancer specialists described the breakthrough as "exciting".

Professor Hume said: "This research provides an incredible resource for the study of immunity and disease in humans and animals. This study has effectively shown us where the brakes are which could slow down or stop diseases like cancer and multiple sclerosis. We believe that this could lead to treatments and cures for many diseases of the immune system."

The scientists said they believed that variations in this network explained why people could develop diseases in different ways.

The team hopes that, by identifying weak spots in the gene structure, they will be able to stop the growth of tumours, enabling the growth of healthy cells.

They also hope the new research could lead to treatments for the likes of myeloid leukaemia and arthritis.

The researchers said the findings offered up previously hidden information about the immune system and could ultimately help doctors understand why some cancer patients responded to immunotherapies while others did not.

Professor Hume, who carried out the three-year study as part of a team of international researchers, focused on the immune system and examined the genes involved with white blood cells called macrophages.

When healthy, these cells cleanse the body of viruses and bacteria, but if they grow uncontrollably, they can turn against the body's own tissue to cause conditions such as MS, arthritis and emphysema.

It was previously thought that such cell-growth processes were managed by a select group of master, or regulator, genes that give instructions to many other genes.

However, the research makes clear that there are, in fact, hundreds of regulator genes which all interact with each other to control cell development and growth. Scientists say it helps to explain why people can develop the same disease in different ways, because of variations in different parts of their genetic networks.

By identifying the weak spots in these networks, it is hoped it will soon be possible to stop the growth of tumours, or enable the growth of healthy cells.

Prof Hume, recognised as an international authority in genome sciences, said last night the study was akin to discovering the function of every single part of a car, whereas before only eight or nine were known.

He added: "The traditional way we have carried out research in this area is to look at one gene at a time. We thought processes like cells growing or dying were controlled by a very small number of master genes, but in fact it's an entire environment that creates the changes, with around 20,000 different elements.

"It means we have a much better understanding of how tumours develop.

"There are literally thousands of different ways of developing a tumour, and every one is likely to be different. That represents a serious challenge for us, but it gives us hope that, depending on how the tumour arises, we can know what therapies will be useful."

He said: "We will be able to understand why different people have different responses to pathogens. If you infect a large number of people with influenza, only a few would get sick – we now know why, and how to prevent it from happening. It will make a significant difference to the way vaccines are used and the way drugs are tested, as we will be able to establish likely side-effects to therapies."

Dr Lesley Walker, director of cancer information at Cancer Research UK, said: "This exciting research reveals just how complex the development of our immune system is – areas of the genome that we thought were dormant may actually play an important role in guiding its evolution."

She added: "The studies may eventually help to explain why some people respond to immunotherapies and others don't."

A spokesman for the Multiple Sclerosis Society Scotland, the charity of which JK Rowling served until recently as patron, said: "Every day, researchers are learning more about the genetic make-up of MS, and anything that helps put the pieces of this complex puzzle together must be a good thing.

"This study also highlights the important role that research in Scotland is playing in developing our understanding of MS and other autoimmune conditions," the spokesman added.

Dr Mark Matfield, scientific adviser for the St Andrews-based Association for International Cancer Research, said: "This is a really powerful new study of how cells work. It shows us the mechanisms controlling how cells change are much more complicated than we thought. It may go some way to explain why it has been so difficult to understand these mechanisms.

"This study only looks at white blood cells, and we'll need to find out if this is generally true in other types of cells," he said. "However, this clearly takes us one big step closer to understanding the way cells grow and change – one of the great questions of medical science."

The discovery is regarded as an important breakthrough for the Roslin Institute, which formed a multi-million-pound partnership with the University of Edinburgh last year. Scientists intend to extend the project with funding from the Biotechnology and Biological Sciences Research Council to look at the way genes communicate to control immunity in livestock animals.

The study was conducted as part of the Functional Annotation of the Mammalian cDNA (FANTOM], a consortium comprising scientists at the Roslin Institute, the RIKEN Yokohama Institute in Japan, and researchers from the US, Canada, Australia, Switzerland, Norway, South Africa, Sweden, Denmark, Italy, Germany, and Singapore.

The main points of the discovery and what it means

1 Scientists probed the genes involved with white blood cells called macrophages, which measure just 21 micrometres in diameter. When healthy, the cells cleanse the human body of bacteria and viruses.

2 Sometimes the macrophages grow uncontrollably, turning against the body's own tissue. This can lead to the development of conditions such as multiple sclerosis, cancer, arthritis, and emphysema.

3 It was previously believed these processes were caused by a small number of master, or regulator, genes. However, the new research reveals there are hundreds of these types of genes, all interacting in tens of thousands of ways.

4 The findings will allow scientists to find out in greater detail how tumours develop. It is hoped they will be able to develop specific therapies depending on how the tumour has formed.

'You mourn for your future'

Sue Polson, 59, noticed she had a numb ankle after working in her garden 11 years ago. When the numbness began to spread up her leg, she visited her doctor who sent her to hospital.

Doctors at Edinburgh's Western General believed she had damaged her spine and carried out a series of tests. She was then sent home and told her problem had been a one-off. But eight months later, the symptoms returned and Mrs Polson was finally diagnosed with relapsing/remitting Multiple Sclerosis (MS). The condition sees a person's immune system attack the central nervous system, leading to physical disability.

"I had a catastrophic attack in 2000 and couldn't walk," she said. "I was in hospital for a long time and had to learn to stand and walk again. I found it very frustrating to give up my career. I was very angry at the time."

She added: "Mentally, it's a huge adjustment. It's the loss of your health and your future and there's a time of mourning because you know there's nothing you can do to stop it."

After that attack Mrs Polson, who now lives in Crossford near Dunfermline, was put on an immunosuppressant drug called Azathioprine which helped manage her condition, though her health continued to deteriorate.

"This new discovery looks fantastic and I look forward to seeing more details," she said. "I would like to be some years younger so I could benefit but I don't care as long as something is happening."

SCOURGE AFFECTS THOUSANDS

Multiple Sclerosis (MS) is the most common disabling neurological condition affecting adults. About 100,000 people in the UK and 10,500 people in Scotland have the condition.

Scotland is known as the MS capital of the world as it has more people with the condition per capita than anywhere else.

MS is the result of damage to myelin – a protective sheath surrounding nerve fibres of the central nervous system. It is split into two types, relapsing/remitting MS, where a person has flare-ups that can result in extreme levels of disability followed by periods of significant recovery, and progressive MS, which is a slower but permanent degeneration.

Diagnosis is 50 per cent more common in woman than men and the average age of diagnosis is the mid-thirties.

Symptoms of MS are varied and can include problems with balance, bladder and bowel, fatigue, memory and concentration difficulties, depression and emotional problems, vision problems, speech difficulties, tremors and swallowing problems.

Source: News.scotsman.com ©2009 Johnston Press Digital Publishing (20/04/09)

Genomics of ethnicity may lead to possible treatment differences in Multiple Sclerosis in caucasians and negros

MS and Genetics

Researchers have assembled the first-ever map of copy number variants (CNV)-- duplications, deletions or rearrangements in the genome that result in different gene copy numbers -- in African Americans. The study, appearing in BMC Genetics, also identified two CNVs that differed in frequency between African American genomes and those in people of European descent.

Joseph McElroy, a postdoc in the lab of neurologist Jorge Oksenberg at the University of California, San Francisco, and lead author, said that the study will provide a baseline informing his lab's future investigations into the genetic underpinnings of multiple sclerosis in African Americans. "The reason we wanted to [compare CNVs in African Americans and whites] is because most of the literature on this has been done in whites," he said. "On a genome-wide level, African Americans haven't been studied for diseases that are present in African American populations."

McElroy and his colleagues screened the genomes of 385 healthy African Americans, and 435 healthy white people primarily from Europe or North America. The researchers found a total of 1972 CNVs in white subjects and 1362 CNVs in African Americans - overall, a statistically insignificant difference. They did pull out two significant differences: a duplication on chromosome 17 that was nearly six times more frequent in whites and another on chromosome 15 that was almost twice as common in whites than in African Americans.

"What they found was not surprising in the sense that African Americans are as variable as Caucasians," said Bob Ferrell, a human geneticist at the University of Pittsburgh who was not involved with the study. "It'll only become important if it turns out that one or more of these regions where blacks and whites differ is related to susceptibility to some disease or genotype."

Unsurprising as they may be, the findings might lay the groundwork for individual or ethnicity-based disease treatments that target unique genetic signatures in patients. Much work remains to be done, however, before such personalized or ethnicity-based therapies become a reality, McElroy said. "I can see that in the far future as being a goal," he said, "but our basic goal is to understand the mechanisms that are causing disease."

CNVs have already been linked to a few complex diseases, such as Crohn's disease, rheumatoid arthritis and diabetes. "It's being recognized that an increasing number of diseases have some contribution from CNVs," noted Ferrell. "I would not be surprised to find out that susceptibility to certain diseases is due to copy number variation, but we don't have a lot of examples."

Ferrell added that another of the study's findings may be more important in the short-term for researchers. McElroy and his group screened DNA from both whole blood and transformed lymphoblastoid cell lines in their subjects and found significant differences in CNV frequencies between the two. "There may be many studies that are flawed or have errors in their conclusions because of this," Ferrell said, noting that the HapMap project, for one, relied only on DNA derived from transformed cell lines. "It would make me very cautious about the use of cell lines."

McElroy said that he is now examining CNV frequency in African Americans with multiple sclerosis and healthy subjects to look for a difference between the two groups. He added that African Americans tend to have a more aggressive form of the disease, even though the overall frequency of MS is lower in the African American population.

Source: The Scientist © 1986-2009 The Scientist (25/03/09)

Genetics studies provide new clues to why people develop MS

MS and Genetics

New studies are deciphering the complex picture of genetic characteristics that make people susceptible to MS, thanks to international collaborations and unique population studies. Each gives important new clues about why people get MS. Additional large-scale studies, the first stages of which are already underway, promise to uncover the great majority of genes that convey risk for MS, which would pave the way for understanding the basic cause of MS and developing more rational therapies.

CD58 Gene: When it completed the largest replicated whole genome scan (scan of all the genes in the body) for MS to date, the International MS Genetics Consortium (IMSGC) identified and validated variations in two genes that help regulate the immune system as clearly increasing genetic susceptibility to MS, and preliminarily identified several other genes of newly suspected importance in MS. Philip De Jager, MD, PhD (Brigham & Women’s Hospital, Boston) and colleagues in the IMSGC now report on one of these other genes, CD58, which instructs the activation of T cells, major players in the immune attack on the brain and spinal cord in MS. They studied this gene in 1530 additional people with MS, and found further evidence of its association with the disease. They pinpointed a specific marker, or segment of DNA, on the gene that is associated with reduced susceptibility to MS. They also showed that the level of CD58 expression (that is, the amount of CD58 protein that is produced from the CD58 gene) is associated with remissions from MS disease activity. Manipulating CD58 is a strategy used in treat other autoimmune diseases, so this study may open up new therapeutic options for people with MS. (Proceedings of the National Academy of Sciences U S A 2009 Feb 23)

KIF1B Gene: Yuri Aulchenko, PhD, Rogier Hintzen, MD, PhD (Erasmus MC University Medical Center, Rotterdam, Netherlands) and colleagues completed a genome-wide study of a unique group – 26 people with MS in the Netherlands who had a common ancestor – a fact unknown to them before the study! They found evidence of heightened risk of developing MS associated with a variant of the gene KIF1B, which is important in the function of nerve cells. The team then sought to confirm these findings in a sample of 2,634 people from the Netherlands, Sweden, and the Canadian Collaborative Project on Genetic Susceptibility to MS, and a group of 2,930 controls without MS. The results strengthened the conclusion that the KIF1B variant is associated with significantly higher risk for developing MS. Since this gene is related to nerve cell function, it may also eventually help to determine why people with MS develop the long-term disability that results from nerve cell damage. (Nature Genetics, advance online publication November 9, 2008)

HLA Genes: Stacy J. Caillier, BSc, Jorge Oksenberg, PhD (University of California, San Francisco) and colleagues have been collecting blood samples from a large number of families affected by MS, funded in part by the National MS Society, focusing on ethnic groups with lower MS susceptibility (e.g., African-Americans) and higher susceptibility (e.g., individuals of Northern European descent), and searching for commonalities and differences that may help pinpoint genes of importance in MS. Here they report an important new finding on HLA genes, which are involved in immune function and have long been associated with MS. The team tackled the problem of how to discern the roles of two different closely related HLA genes – HLA-DRB1 and HLA-DRB5 – by studying a dataset of 1635 African-Americans, including 769 people with MS. They found that HLA-DRB1 is associated with MS susceptibility even in the absence of HLA-DRB5, indicating that the former is the primary gene relating to susceptibility. People without HLA-DRB5 were at increased risk of developing secondary-progressive MS, however, so this gene may protect against disease progression. (The Journal of Immunology 2008 Oct 15;181(8):5473-80)

GPC5 Gene: This same team completed a genome-wide study of genetic variations in 978 people with MS and 883 controls without MS. One of their most compelling findings is a link between the GPC5 gene with MS risk. This gene is implicated in nerve fiber regeneration, and previous work by this team suggested that variations in the gene may also help determine a person’s response to interferon beta therapy. The team also found that genes relating to MS susceptibility were separate from those linked to disease course. (Sergio E. Baranzini, PhD, et al, Human Molecular Genetics 2009 Feb 15;18[4]:767-78)

“Each of these studies give us important new clues to why people get MS and even why it may progress,” said John Richert, MD, Executive Vice President of Research and Clinical Programs for the National MS Society. “Of the genes identified so far, some function within the immune system and some are related to nervous system function. There is increased excitement and opportunity to study the many genes related to susceptibility and severity of MS”, he added. “In fact, we’re currently raising funds for a new international, large-scale study, the first stages of which are underway, that promises to uncover most of the remaining genes that convey risk for MS. This would pave the way for understanding its root causes and for developing more rational therapies and even prevention.”

Source: The US National MS Society (06/03/09)

Amino acid that could be a major risk factor for Multiple Sclerosis indentified

MS and Genetics

An elaborate statistical analysis of genes from more than 7,000 individuals has identified an amino acid that appears to be a major risk factor for multiple sclerosis, a devastating autoimmune disorder that afflicts 2.5 million people worldwide.

In research published this month in BMC Medical Genetics , scientists from The Rockefeller University and colleagues from the University of Oxford in England and the University of British Columbia in Canada report a binding pocket in a previously implicated gene that may be an attractive research prospect as a potential drug target.

The analysis by biostatistician Knut M. Wittkowski, of Rockefeller's Center for Clinical and Translational Science, is the most sweeping to date of a database containing disease-relevant genes of 13,000 individuals who either have multiple sclerosis or are closely related to someone who does. Wittkowski and colleagues focused on a gene identified about a year ago in the New England Journal of Medicine as the single most important genetic risk factor for multiple sclerosis. The gene, HLA-DRB1 , is part of the major histocompatibility complex, a large cluster of particularly complex genes evolved to help the immune system adaptively respond to foreign invaders that it has never before encountered. How it contributes to the disease remains a mystery, however.

Unlike most human genes, which have only two alleles per locus, HLA-DRB1 has up to four, making traditional statistical analyses problematic. Wittkowski extended a variant of a commonly used method he developed in 2002 with a postdoc from Rockefeller's Laboratory of Statistical Genetics to deal with multi-allelic loci so that it could handle the complexity of HLA-DRB1 . He analyzed 93 locations with genetic variations and found that a single amino acid in the protein that the gene encodes, number 13, is the telltale indicator of susceptibility to multiple sclerosis. Amino acid 13 is at the center of a pocket in the HLA-DRB1 molecule that helps present an invading pathogen to the immune cells that can kill it. The researchers speculate that a mutation in this amino acid could cause the molecule to present healthy tissue for execution, one of the possible ways multiple sclerosis attacks the body.

"We have identified the most important part of the gene for MS risk," says Sreeram Ramagopalan, a postdoctoral research fellow at Oxford's Wellcome Trust Center for Human Genetics, who collaborated with Wittkowski. "And it looks plausible. Amino acid 13 is part of a piece of the molecule that presents peptides to trigger the immune reaction."

Although multiple sclerosis is a complicated disease that likely has other genetic as well as environmental risk factors, the collaboration between Wittkowski and clinical and translational colleagues has provided researchers a specific hypothesis to explore. "It is rare to find investigators who are open to developing new statistical methods to address the data at hand," Wittkowski says. "This is the type of transformative result a real collaboration can produce beyond the more common consultation about off-the-shelf methods."

Ramagopalan says his researchers at Oxford will be following up on the statistical analysis with wet-lab experiments using animal models to detail the role amino acid 13 plays. "Now we want to know exactly how it works and what happens without it or when it is changed," he says.

Source: News-Medical.Net © 2009 News-Medical.Net (16/02/09)

Modification of Multiple Sclerosis phenotypes by african ancestry at HLA

Genetics and MS

Background:  In those with multiple sclerosis (MS), African American individuals have a more severe disease course, an older age at onset, and more often have clinical manifestations restricted to the optic nerves and spinal cord (opticospinal MS) than white persons.

Objective:  To determine whether genetic variation influences clinical MS patterns.

Design:  Retrospective multicenter cohort study.

Participants:  Six hundred seventy-three African American and 717 white patients with MS.

Main Outcome Measures:  Patients with MS were genotyped for HLA-DRB1 and HLA-DQB1 alleles. The proportion of European ancestry at HLA was estimated by genotyping single-nucleotide polymorphisms with known significant frequency differences in West African and European populations. These genotypes were correlated with the opticospinal disease phenotype, disability measures, and age at onset.

Results:  Subjects with DRB1*15 alleles were twice as likely to have typical MS rather than opticospinal MS (P = .001). Of the subjects with opticospinal MS or a history of recurrent transverse myelitis who were seropositive for anti–aquaporin 4 antibodies (approximately 5%), none carried DRB1*15 alleles (P = .008). Independently of DRB1*15, African ancestry at HLA correlated with disability as measured by the Multiple Sclerosis Severity Score (P < .001) and risk of cane dependency (hazard ratio, 1.36; P < .001); DRB1*15 alleles were associated with a 2.1-year earlier age at onset (P < .001).

Conclusions:  These data indicate that the role of HLA in MS is not limited to disease susceptibility but that genes embedded in this locus also influence clinical outcomes.

Bruce A. C. Cree, MD, PhD, MCR; David E. Reich, PhD; Omar Khan, MD; Philip L. De Jager, MD, PhD; Ichiro Nakashima, MD; Toshiyuki Takahashi, MD; Amit Bar-Or, MD; Christine Tong, BS; Stephen L. Hauser, MD; Jorge R. Oksenberg, PhD

Author Affiliations: Department of Neurology, University of California–San Francisco, San Francisco (Drs Cree, Hauser, and Oksenberg, and Ms Tong); Department of Genetics, Harvard Medical School, Cambridge, Massachusetts (Dr Reich); Department of Neurology, Wayne State Medical School, Detroit, Michigan (Dr Khan); Harvard Medical School/Partners Healthcare Center for Genetics & Genomics, and Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital, Boston (Dr De Jager); Department of Neurology, Tohoku University School of Medicine, Sendai, Japan (Drs Nakashima and Takahashi); and Montreal Neurological Institute, McGill Medical School, Montreal, Quebec, Canada (Drs Nakashima and Bar-Or).

Source: Archives of Neurology 2009;66(2):226-233. (10/02/09)

Scientists seek volunteers for part two of multiple sclerosis research

Scottish Flag

Scientists working on a major study into the causes of multiple sclerosis (MS) are appealing for volunteers from Shetland to take part in the second phase of their work.

Funded by the MS Society and led by Dr Jim Wilson of the Uni­versity of Edinburgh and Dr Eliza­beth Visser of the University of Aberdeen, the research aims to find a correlation between MS and genes and, specifically, whether an “MS gene” exists. The first phase of the study was launched last year and is progressing well, according to Dr Wilson.

Clinical research fellow on the project Dr Visser, a neurologist, has been in Shetland a number of times dealing with volunteers who came forward for the first phase and will be here every month for a week at a time until the autumn to conduct the next stage of the work.

Currently around one in every 250 people in Shetland and Orkney suffers from the condition. This figure is around double that of the Scottish mainland average, putting Shetland and Orkney in the unfor­tunate position of having the highest rates in the world.

Dr Wilson, originally from Ork­ney, said: “It’s not unlikely that there may be undiscovered genes in Ork­ney and Shetland as [the prevalence of MS] is so high.”

The link between genes and medical conditions can be extremely important. Dr Wilson explained: “Finding the genes which increase the risk of developing the disease is the first step to finding new treatments.”

The second phase of the research requires comparison with non MS patients. To do this, the study is recruiting volunteers to act as “controls”, so that their DNA can be related to the genes carried by people with MS.

Dr Wilson said: “By this I mean a group of people who share certain characteristics with the MS patients – for example being the same age and sex, and coming from Shetland, so we can compare the DNA of the patients with that of the matched comparison group.”

To do this they are looking for people who are from Shetland, born between 1930 and 1990 and have no family members with MS. If you would like to help with the study, call 0131 651 1643 or email '); document.write(addy80896); document.write('<\/a>'); //-->\n This email address is being protected from spambots. You need JavaScript enabled to view it. " href="mailto: This email address is being protected from spambots. You need JavaScript enabled to view it. "> This email address is being protected from spambots. You need JavaScript enabled to view it. .

An appointment to meet Dr Visser will be made, where she will go through a short questionnaire and take a blood test.

Dr Visser explained what a volunteer can expect: “We’ll have a bit of a chat about their medical history and do the questionnaire which we’ve created, basically to make sure they don’t have MS,” she said. “The first 10 or so controls will be examined and then we’ll take a small blood test. This can be done at their GP or at home.”

MS is a chronic auto-immune disease caused by damage to myelin, the protective sheath which sur­rounds the spinal cord and central nervous system. This leads to dis­ruption to the nerve signals that control muscle co-ordination, strength, sensation and vision.

It is the most common debilitating neurological disease in the UK, affecting around 100,000 people.

Despite the frequency of cases, the range and complexity of symp­toms which can occur means there is no single diagnostic test for the disease.

Other conditions with similar symptoms often have to be ruled out, however some of the tests which can lead to diagnosis include MRI scans, neurological examinations and lumbar puncture, in which spinal fluid is examined for abnormalities.

The variety in symptoms and their severity often means different experiences for each person, how­ever it usually means life is unpredictable.

The study has been welcomed by the members of the community.

Ann MacLellan, 66, from Lerwick, was diagnosed with MS 24 years ago. She said: “A lot of folk have wondered why something’s not been done before as there are so many people affected by it.”

Despite the length of time she has suffered, Mrs MacLellan’s symp­toms have been manageable. “Really I’ve kept very well, I’ve been lucky, other than if I overdo it my legs get weak. That and the tiredness. But a lot of folk wouldn’t know I had it.”

However for Ian Richardson, 52, from Unst, MS has had a huge impact on day to day life.

“It’s affected everything. It defines how you live, whether you want it or not,” he said.

Diagnosed five years ago, his symptoms vary from time to time, with the worst periods preventing him from getting up the stairs.

However while mobility is a huge issue, there are other sides to the disease.

Mr Richardson explained: “The major problem that develops is your ability to deal with it. The mental attack is often worse than the physical, the drain of knowing you can’t do simple tasks.”

He continued: “I don’t like having to ask for things, but I have to. The little things become more important; it’s the frustration of that.”

However Mr Richardson said he is “very impressed” with the standard of service provided in Shetland.

He said: “Not just for MS, with anything of this type, it’s one of the best places to be. The entire house was fitted out with grab-bars and the MS Society locally has assisted me a great deal.”

Speaking about the study itself, Mr Richardson said: “Anything that develops a better knowledge of it and lead to the golden aim of destroying it is a great thing. It all helps.”

Dr Wilson and his team are, at the moment, primarily looking for people who do not have any cases of MS in their family, but he advised that anyone who does and would like to help should encourage their friends or neighbours to get involved.

Dr Visser continued: “The study is very important as the disease is very common in Orkney and Shetland, so it will be interesting to see if there is anything special [which would] make people more prone to it in the area.

“I’d just like to say a big thank you to everyone who’s been involved so far. We’re very grateful, we’ve had a remarkable response. If anyone would like to be involved or help, now is the time to say. We’re very excited about this study and we’re really hoping it will reveal a bit more about MS.”

Source: The Shetland Times © 1996–2008 The Shetland Times (23/01/09)

Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis

Genes and MS

The role of genes in the pathogenesis of MS is complex. The authors found an association between a gene called Atg5 and MS, suggesting that it may contribute to inflammation in MS.

Multiple sclerosis (MS) is an inflammatory central nervous system (CNS) disorder characterized by T cell-mediated demyelination. In MS, prolonged T cell survival and increased T cell proliferation have been linked to disease relapse and progression.

Recently, the autophagy-related gene 5 (Atg5) has been shown to modulate T cell survival. In this study, we examined the expression of Atg5 using both a mouse model of autoimmune demyelination as well as blood and brain tissues from MS cases.

Quantitative real-time PCR analysis of RNA isolated from blood samples of experimental autoimmune encephalomyelitis (EAE) mice revealed a strong correlation between Atg5 expression and clinical disability.

Analysis of protein extracted from these cells confirmed both upregulation and post-translational modification of Atg5, the latter of which was positively correlated with EAE severity. Analysis of RNA extracted from T cells isolated by negative selection indicated that Atg5 expression was significantly elevated in individuals with active relapsing-remitting MS compared to non-diseased controls.

Brain tissue sections from relapsing-remitting MS cases examined by immunofluorescent histochemistry suggested that encephalitogenic T cells are a source of Atg5 expression in MS brain samples. Together these data suggest that increased T cell expression of Atg5 may contribute to inflammatory demyelination in MS.

Authors: Alirezaei M, Fox HS, Flynn CT, Moore CS, Hebb AL, Frausto RF, Bhan V, Kiosses WB, Whitton JL, Robertson GS, Crocker SJ - Autophagy. 2009 Feb 5;5(2).

Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California, USA.

Source: PubMed PMID: 19066443 (21/01/09)

Heritability of traits and diseases may not be limited to DNA

image

A new study conducted by scientists at the Centre for Addiction and Mental Health (CAMH) suggests that DNA may not be the only carrier of heritable information, and that a secondary molecular mechanism called epigenetics may also account for some inherited traits and diseases.

The researchers say that their findings challenge the fundamental principles of genetics and inheritance, and potentially provide a new insight into the primary causes of human diseases.

A trait or disease is called heritable if genetically identical twins are more similar to each other than genetically different twins.

In molecular terms, heritability has traditionally been attributed to variations in the DNA sequence.

Dr. Art Petronis, head of the Krembil Family Epigenetics Laboratory at the CAMH, conducted a comprehensive epigenetic analysis of 100 sets of genetically identical and genetically different twins in the first study of its kind.

“We investigated molecules that attach to DNA and regulate various gene activities. These DNA modifications are called epigenetic factors,” said the lead researcher.

His study demonstrated that epigenetic factors - acting independently from DNA - were more similar in identical twins than their non-identical counterparts, suggesting that there was a secondary molecular mechanism of heredity.

The epigenetic heritability might help explain currently unclear issues in human disease, such as the presence of a disease in only one identical twin, the different susceptibility of males (e.g. to autism) and females (e.g. to lupus), significant fluctuations in the course of a disease (e.g. bipolar disorder, inflammatory bowel disease, multiple sclerosis), among numerous others.

“Traditionally, it has been assumed that only the DNA sequence can account for the capability of normal traits and diseases to be inherited,” says Dr. Petronis.

“Over the last several decades, there has been an enormous effort to identify specific DNA sequence changes predisposing people to psychiatric, neurodegenerative, malignant, metabolic, and autoimmune diseases, but with only moderate success. Our findings represent a new way to look for the molecular cause of disease, and eventually may lead to improved diagnostics and treatment,” the researcher added.

The study has been published in the online edition of the journal Nature Genetics.

Source: Skyblue.in © 2009 Skyblue.in. (21/01/09)

Genomic NGFB variation and multiple sclerosis in a case control study

Genetics and MS

Nerve growth factor beta (NGFB) is involved in cell proliferation and survival, and it is a mediator of the immune response. ProNGF, the precursor protein of NGFB, has been shown to induce cell death via interaction with the p75 neurotrophin receptor.

In addition, this neurotrophin is differentially expressed in males and females. Hence NGFB is a good candidate to influence the course of multiple sclerosis (MS), much like in the murine model of experimental autoimmune encephalomyelitis (EAE).

Methods: Ten single nucleotide polymorphisms (SNPs) were genotyped in the NGFB gene in up to 1120 unrelated MS patients and 869 controls.

Expression analyses were performed for selected MS patients in order to elucidate the possible functional relevance of the SNPs.

Results: Significant association of NGFB variations with MS is evident for two SNPs.

NGFB mRNA seems to be expressed in sex and disease progression-related manner in peripheral blood mononuclear cells.

Conclusions: NGFB variation and expression levels appear as modulating factors in the developmentof MS.

Authors: Denis A Akkad, Niels Kruse, Larissa Arning, Ralf Gold and Joerg T Epplen

Source: BMC Medical Genetics 2008, 9:107 (09/12/08)

Neuron gene linked to multiple sclerosis

image

A newly-discovered genetic flaw may lay the nervous system open to assault from the body's own immune system, leading to multiple sclerosis (MS).

In MS, the immune system attacks myelin, the fatty sheath that protects the cells of the central nervous system.

As a result, nerve signals get slowed or blocked, causing difficulties in movement and coordination, muscle weakness, cognitive impairment, slurred speech and vision problems. There is no known cure.

Scientists have known for three decades that the disease has a genetic cause, but the mechanism has remained obscure.

The new find -- the product of eight years' work -- is a variant of a gene known as KIF1B.

Trolling through municipal and church records, a team led by Rogier Hintzen of the Erasmus Medical Centre in Rotterdam found 26 MS patients in southern Holland who -- unbeknownst to them -- all had a common ancestor dating back to the early 18th century.

The researchers then scanned each individual's genomes to see if they shared any genetic anomalies.

"We found a peak in the KIF1B gene, which was very exciting because its function is well known and fits so well," said Hintzen.

The handful of genes previously known to be implicated in the debilitating disease all help shape the defence mechanism our bodies use to ward off infection.

But KIF1B plays a critical role in the transport of signals along metre-long (yard-long) neurons between the brain and the spinal cord, said Hintzen.

Their length makes them particularly vulnerable to damage or attack.

After gaining this nugget of knowledge, Hintzen then cast the same genome-wide net among 2,597 individuals with MS from the Netherlands, Sweden and Canada, and compared the data to an even larger control group.

The results showed a slightly higher risk of MS when the suspect gene variant was present.

"But what makes this find spectacular is that it points to a pathway that was unknown, and that must be involved in the pathological process," Hintzen said.

"It makes perfect sense, because this gene is a kind of motor for transport in neurons."

The study, published in the journal Nature Genetics, suggests that the suspect variant may account for the divergent outcomes.

"It is probably the way the nerve tissue deals with the attack that makes the difference," said Hintzen.

If so, the variant could become a target for drug therapies, he said.

The next step is to design clinical trials that will test the presence of the variant in both sub-groups of MS sufferers -- those with the one-off episode of the disease and those with the degenerative form.

With luck, this will confirm the precise mechanism that removes the shield protecting the nervous system.

MS affects millions of people worldwide, including almost 100,000 in Britain and 400,000 in the United States.

Source: Physorg.com © 2008 AFP (10/11/08)

Functional polymorphism associated with Multiple Sclerosis

Genes and MS

This technology has identified a genetic marker to aid in the diagnosis of patients with multiple sclerosis as well as to identify patients whom have an increased risk of developing the disease.

Detailed Description:

Description of Technology/Products:
Multiple Sclerosis (MS) is a progressive adult disorder of the nervous system affecting an estimated 400,000 Americans. MS is thought to be an autoimmune disease, in which the bodies’ immune system attacks its own nerve cells in central nervous system. Neurons are surrounded by a protective fatty layer called myelin. MS causes demyelination or a gradual destruction of myelin and transection of neuron axons in patches throughout the brain and spinal cord. The name multiple sclerosis refers to the multiple scars (or scleroses) on the myelin sheaths. This scarring causes symptoms which vary widely depending upon which signals are interrupted. Some symptoms include pain, numbness, and loss of strength, vision defects and other symptoms.

Currently there is no cure for the disease and available treatments work to slow the onset of symptoms. In addition MS is difficult to diagnose in its early stages. In fact, definite diagnosis of MS cannot be made until there is evidence of at least two anatomically separate demyelinating events occurring at least thirty days apart. Thus patients and physicians may benefit from early diagnosis.

These researchers have identified a genetic polymorphism IL7R that is associated with multiple sclerosis. This polymorphism influences the amount of soluble and membrane bound IL7R protein. Since IL7 enhances the antigenic T cell response to myelin this discovery may also serve as a possible therapy as well as a genetic marker for either the predisposition of the disease or as a diagnosis for the disease.

Source: iBridge copyright 2008, Kauffman Innovation Network, Inc. (03/10/08)

Vitamin D Linked to Genetic, Environmental Risk for Multiple Sclerosis

Vitamin D

Results from a new study unite the genetic and environmental risks of multiple sclerosis in a disease-specific and gene-environment interaction. Presenting at the American Neurological Association 133rd Annual Meeting, researchers described a link between vitamin D and the pathogenesis of MS.

"There's a connection between the 2 — no question about it," lead investigator George Ebers, MD, from the University of Oxford, in the United Kingdom, told Medscape Neurology & Neurosurgery. "But exactly how it works is not clear yet."

Asked to comment on the work, Emmanuelle Waubant, MD, from the University of California, San Francisco said, "MS is a very heterogeneous disease, and this is an interesting way to look at the factors that predispose people."

She noted, "This study looks at the bigger picture and is the way things should be done. The data provide decent traction and it is an interesting result."

Dr. Ebers and his team examined the major histocompatibility complex (MHC) for deoxyribonucleic acid (DNA) sequences predicted to respond to vitamin-D complexes.

They identified a single sequence, which appeared to be functionally active because it transfected the segment into cell lines and measured functional expression in response to added vitamin D.

Unexpectedly, they found this sequence is haplotype-specific and perhaps evolving in response to selective pressures characterizing the northern migration of European populations.

This solitary MHC vitamin-D–responsive element is strategically located in the promoter region of the class II complex specific to a haplotype associated with MS risk, Dr. Ebers told the meeting.

"These findings further implicate vitamin D in environmentally mediated MS risk," he said.

Sequence Haplotype-Specific

During an interview after the session, Dr. Ebers said his group was surprised by what it found. "Most times you don't find exactly what you are looking for, but in this case, that is exactly what we found. It was as plain as day."

The data suggesting vitamin D is deficient in MS are strong, Dr. Waubant added. "What is unclear is whether or not it also affects the severity of disease."

"Everyone who has examined this from the National Academy of Sciences to the dietary committee of the European Union to a variety of professional organizations all agree pretty much that the amount of vitamin D that people are getting is too low," Dr. Ebers pointed out.

"I know all the experts in the field, and they've sort of voted with their feet," he said. "They're all on vitamin D and their family is on it too. As far as anyone can tell, the amounts in question are harmless, and it's dirt cheap."

Some experts are advocating that given the potential benefit, vitamin D should be widely administered. But others have reservations and are recommending a more cautious approach.

"I'm reluctant to say there's absolutely no risk, because people have been wrong on these things," Dr. Ebers told Medscape Neurology & Neurosurgery. "But I think in this particular case, the evidence has been so strong that it's safe, and all the experts who examine this are comfortable. Plus, many are giving 2000 units a day to pregnant women, so that should be as reassuring as anything."

This study was funded by the Scientific Foundation of the Canadian MS Society and the UK MS Society.

Source: MedScape Medical News (28/09/08)

European network to investigate gene causing multiple sclerosis

MS and Genetics

Ten research teams will investigate the genetic component of the multiple sclerosis’ treatment, they will do it from the University of the Basque Country.

The University of the Basque Country hosted a conference in which lecturers introduced the European scientific network that will look into the new customized treatments for multiple sclerosis. The talk took place at the so-called “Classrooms of the Experience” located at University’s premises in the old part of Bilbao’s city.

The multiple sclerosis is a chronic neurological disease with no definitive cure. It currently affects 400,000 people in Europe, 2,000 in the Basque Country.

During the presentation it was possible to listen to the Belgian professor Koen Vandenbroeck ‘s speech. Vanderbroek is a scientist that works for Ikerbasque, a Foundation created by the Basque Government that primarily aims to help develop scientific research in the Basque Country by attracting researchers and helping them establish themselves in the field of research. Belgian researcher will be the main coordinator of the study.

A European scientific network will investigate the genetic component of the multiple sclerosis’ treatment and it will do it from the Basque University. Ten research teams from five different countries will work on a 2, 3 million Euro-project during four years. The aim is to use genetics to advance towards a customized medication.

The project also offers training internships intended for young researchers.

Source: eitb24 © eitb24 - 2008 (23/09/08)

Parent of origin in multiple sclerosis: Understanding inheritance in complex neurologic diseases

MS and Genetics

Multiple sclerosis (MS) is a complex disease with a heterogenous phenotype resulting from interaction of multiple genetic and environmental factors. In this issue of Neurology®, Herrera et al.1 conclude that patients with MS who have unaffected parents have a higher number of maternal than paternal uncles or aunts with MS.

This finding supports previous studies that have shown a parent-of-origin effect operating through the maternal lineage .2,3 Halfsibling pairs with MS who have unaffected parents were more likely to be related through their mothers than their fathers.2 In a Dutch multigenerational pedigree with a strong founder effect, the 24 patients with MS were more likely to be related to each other through a maternal lineage than a paternal lineage.3 However, when patients with MS with affected parents were studied, mother– child pairs with MS were less frequent than expected and father– child pairs with MS were more frequent than expected.4 In a population-based cohort, no parent-of-origin effect in transmission of disease from affected parent to offspring was observed.5 All of these studies attempted corrections for the known increased risk of MS in women.1-5 All are limited in that they fail to account for up to 10% of the biologically affected first-degree relatives with MRI activity in the absence of clinical disease (i.e.,asymptomatic MS).6

Whenever affected parent– child pairs are left out of the model, there seems to be maternal transmission of MS, and whenever affected parent– child pairs are directly studied at the nuclear family level, paternal transmission seems to catch up or even exceed maternal transmission.1-5 This observation could be due to technical differences between studies.

Opposing transmission models (maternal vs paternal) in individual families in the population-based study could be diluted by inclusion of many small families. On the other hand, the smaller sample sizesof all of the other studies could introduce potential biases toward enrichment of either the paternal or maternal inheritance models.

The presence of a parent-of-origin effect suggests several possible biologic mechanisms that may operate differently in alternative models of inheritance of MS. It is possible that there is a threshold effect due to an increased number of penetrant susceptibility genes in a given parental lineage. It is also possible that there are epigenetic mechanisms involved in direct disease transmission from an affected parent. Epigenetics refers to chromatin and DNA modifications, such as histone acetylation and DNA methylation, that affect gene expression.

These DNA modifications are transmitted through cell division but do not involve changes in the underlying DNA sequence of the organism.7 Epigenetic changes occurring early in life could directly contribute to the risk of a disease by affecting the availability of the critical gene product alone or by modifying the risk associated with a given gene polymorphism. In singlegene disorders (e.g., Angelman and Prader–Willi syndromes), imprinting is the mechanism behind the differential parent-of-origin effects observed.8

In complex neurologic disorders such as MS, it is likely that the multifactorial threshold and epigenetic models of inheritance are operating in conjunction. The lack of full concordance for MS between monozygotic twins who share all of their genetic code and most of their early-life environmental exposures suggests that there are potential epigenetic mechanisms operating even before birth.9 Although it is easier to conceptualize direct in utero exposure of the fetus to maternal environment early in life, environmental exposure of the father and even the paternal grandfather can modify multigenerational risk of complex traits such as obesity.10

This is a new and exciting era in our understanding of complex neurologic diseases. It is likely that analysis of epigenetic alterations in DNA will provide information independent of or in addition to the information available from ongoing genetics research and point to novel disease mechanisms. However, while some epigenetic effects may be studied in DNA from peripheral blood cells, epigenetic effects may also operate only in the target tissue, thus requiring establishment of large collections of DNA from relevant tissues.7

REFERENCES
1. Herrera BM, Ramagopalan SV, Lincoln MR, et al. Parentof-origin effects in MS: observations from avuncular pairs. Neurology 2008;71:799–803.
2. Ebers GC, Sadovnick AD, Dyment DA, et al. Parent-of origin effect in multiple sclerosis: observations in halfsiblings. Lancet 2004;363:1773–1774.
3. Hoppenbrouwers IA, Liu F, Aulchenko YS, et al. Maternal transmission of multiple sclerosis in a dutch population. Arch Neurol 2008;65:345–348.
4. Kantarci OH, Barcellos LF, Atkinson EJ, et al. Men transmit MS more often to their children vs women: the Carter effect. Neurology 2006;67:305–310.
5. Herrera BM, Ramagopalan SV, Orton S, et al. Parental transmission of MS in a population-based Canadian cohort[see comment]. Neurology 2007;69:1208–1212.
6. De Stefano N, Cocco E, Lai M, et al. Imaging brain damage in first-degree relatives of sporadic and familial multiple sclerosis [see comment]. Ann Neurol 2006;59:634–639.
7. Hatchwell E, Greally JM. The potential role of epigenomic dysregulation in complex human disease. Trends Genet 2007;23:588–595.
8. Soejima H, Wagstaff J. Imprinting centers, chromatin structure, and disease. J Cell Biochem 2005;95:226–233.
9. Ebers GC. A twin consensus in MS [comment]. Multiple Sclerosis 2005;11:497–499.
10. Pembrey ME, Bygren LO, Kaati G, et al. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 2006;14:159–166.

Source: MSNewschannel.com (10/09/08)

Multiple Sclerosis genetics consortium moves forward

MS and Genetics

In 2007, the International MS Genetics Consortium, which the National MS Society helped to create, published the results of a trailblazing study in which they analyzed 3,000 genetic samples — from 1,000 people with MS and their parents — in a quest to identify what they all had in common, gene-wise.

The consortium identified nearly a dozen such variations, and flat-out confirmed three of them.

Now the consortium has spawned two sub-groups, one based in England and one in the United States, which will take the next steps: two mammoth studies, each scrutinizing the DNA of 10,000 people who have MS and 10,000 who don’t. That’s a total of 40,000 samples, half to be collected in Europe and half in America. Since the first study of 3,000 samples involved the analysis and interpretation of more than 1.5 billion data points, another 12 billion data points are expected. All of them need to be examined to identify new risk factors in MS.

The Wellcome Trust is funding the European side. The National MS Society is soliciting donations for the American part, which is expected to cost about $3 million. If successful, the work could result in earlier diagnosis of MS as well as individualized treatments that hone in on a specific patient’s needs.

“If there was a genetic variation in certain individuals with MS, then you could create a therapy that would target against that,” said Patricia O’Looney, PhD, the Society’s vice president of biomedical research.

“It’s not just wishful thinking; it’s reality. There’s a small clinical trial that is already targeting one of these genetic variations that was identified as a possible risk factor in MS,” she added.

There are two reasons this work is possible, one technological and one human. In 2001, the Human Genome Project led to the advent of an improved gene chip — a special computer processor used in genetics studies — capable of analyzing 500,000 genetic markers simultaneously. Then in 2003, Harvard researcher David A. Hafler, MD, won the Society’s Palmer Collaborative Center Award and used it to draw more than a dozen of the world’s leading geneticists into the MS movement.

“This is what was missing 10 years ago — having the genetics people talk to one another,” O’Looney said.

The declining cost of computing also helps. “Something like this would have cost $10 million or $15 million five years ago,” O’Looney said.

Why two huge studies instead of one? “When you do a large study like this, it’s always important to do a validation and replication study,” O’Looney said. “If something comes out of the Wellcome Trust but doesn’t get replicated, it will be meaningless.”

The fact that the U.S. team is backstopping the British team in no way makes its work less important, O’Looney said. Dr. Hafler’s vision of a global scientific community pooling time and talent to shake loose the genetic secrets of MS only grows.

“It’s all one big happy consortium,” she said. “No one’s working in silos.”

Source: National MS Society (USA) (05/09/08)

High risk of conversion to multiple sclerosis predicted by gene activity

Genes and MS

Scientists have identified a pattern of gene activity that predicts which patients who experience the first clinical symptoms of multiple sclerosis – known as clinically isolated syndrome – are at high risk of converting to the full blown disease.

The finding, reported in the current issue of Proceedings of the National Academy of Sciences ( Aug. 5, 2008 ), identifies potential candidates who may benefit from early therapy for preventing conversion to multiple sclerosis, the researchers say. It also reveals a genetic landscape for studying the earliest molecular events of the disease.

“This is a very exciting development,” says the senior author of the study, Sergio E. Baranzini, PhD, assistant professor of neurology and a member of the Multiple Sclerosis Research Group at University of California, San Francisco.

Currently, there is no definitive way of predicting whether patients who present with clinically isolated syndrome will convert to multiple sclerosis. Magnetic resonance imaging of the brain is key in the diagnosis and clinical surveillance of MS, but it is only moderately effective in forecasting conversion in CIS patients. There also are no known biological markers in the spinal fluid or blood that accurately predict conversion to MS.

“This creates a dilemma for neurologists,” says Baranzini. “They don’t know when – or if – to begin treatment. If neurologists knew which patients were at high risk for rapid progression to MS, they could treat them with disease-modifying therapy that appears to be beneficial in early MS.”

Patients with clinically isolated syndrome experience a single neurological insult, such as vision or gait problems, that lasts for several days. The symptoms result from an attack by cells of the immune system on myelin, the sheath that insulates nerve cells in the central nervous system. The attack, which disrupts communication between nerve cells, is the hallmark of multiple sclerosis. Approximately one third of CIS patients progress to relaxing-remitting multiple sclerosis, the most common form of the disease, within a year, and about half do so after two years. An estimated 10 percent remain free of further attacks forever.

In the study, led by Jean-Cristophe Corvol, PhD, at the time a postdoctoral fellow in the Baranzini lab, the UCSF team set out to examine the genes expressed in the immune system’s CD4+ T cells, which are known to be one of the key culprits in the attack against myelin. They obtained CD4+ T cells from blood samples of 37 patients who had just been diagnosed with CIS and 29 healthy people, or “controls.” Then, using a technique known as microarray analysis, a computational technique that reveals gene activity on a glass slide, they documented the pattern of genes expressed at the time of diagnosis and after one year. They also followed the patients clinically and with MRI for at least 30 months, so by end of the study they knew which converted to MS and which did not.

The researchers first focused on the circa 1,700 genes in patients’ CD4+ T cells whose expression varied most across all samples. They then honed in on 975 genes that showed a distinct molecular signature between CIS patients and healthy controls.

On the basis of how actively genes were transcribed, the genes segregated CIS patients into four distinct subgroups. Significantly, patients in “subgroup 1,” representing 108 genes, converted to multiple sclerosis much more quickly than those in the other groups and had a much higher risk of conversion.

“Remarkably, 100 percent of the patients in subgroup 1 converted to MS within nine months,” says Baranzini. “In contrast, only 20 percent of patients from the other groups converted in the same period of time. And even after 30 months, only 50 percent of them converted.”

Of particular note, a gene known as TOB1 was consistently down regulated, in sub group 1. TOB1 normally functions as a key regulator of CD4+ T cell proliferation. When it is normally expressed, it prevents cells from proceeding through their cell cycle, a process that culminates with the cells dividing and proliferating.

“The fact that the gene is less active in these cells suggests that CIS patients at high risk of conversion have impaired regulation of CD4+ T cell quiescence, possibly resulting in earlier activation of pathogenic CD4+ T cells,” says Jorge R Oksenberg PhD, another key member of the study.

“We’re not sure if what we’re seeing is a cause or earlier molecular effect already going on in these patients. Regardless, we believe TOB1 is part of a signature that together with other cell cycle genes suggests a pathway for therapeutically targeting patients with CIS.”

Other co-authors of the study were Daniel Pelletier, MD; Stacy J. Caillier, BSc; Joanne Wang, MPH; Derek Pappas, PhD; Simona Casazza, PhD; Darin T. Okuda, MD, and Stephen L. Hauser, MD, all of the UCSF Department of Neurology, and Roland G. Henry, PhD, UCSF Department of Radiology.

The study was funded by the National Multiple Sclerosis Society.

Source: Media Newswire (c) Media-Newswire.com (11/08/08)

A first stage genome-wide screen for regions shared identical-by-descent in Hutterite families with multiple sclerosis

The complexity of multiple sclerosis (MS) genetics has made the search for novel genes using traditional sharing methods problematic.

In order to minimize the genetic heterogeneity present in the MS population we have screened the Canadian MS population for individuals belonging to the Hutterite Brethren.

Seven Hutterites with clinically definite MS were ascertained and are related to a common founder by eight generations. Six of the 7 affected individuals and 21 of their unaffected family members (total = 27) were genotyped for 807 markers.

Haplotypes were then inspected for sharing among the six MS patients. There were three haplotypes shared among all six MS patients. The haplotypes were located at 2q34-35, 4q31-32, and 17p13. An additional 15 haplotypes were shared among five of the six Hutterites MS patients.

The HLA Class II region was one of the highlighted regions; however, the shared MHC haplotype bore the DRB1*04 allele and not the MS-associated DRB1*15 allele providing further evidence of the complexity of the MHC.

Additional genotyping to refine the haplotypes followed by screening for potential variants may lead to the identification of a novel MS susceptibility gene(s) in this unique population. (c) 2007 Wiley-Liss, Inc.

Dyment DA, Cader MZ, Datta A, Broxholme SJ, Cherny SS, Willer CJ, Ramagopalan S, Herrera BM, Orton S, Chao M, Sadovnick AD, Hader M, Hader W, Ebers GC.
The Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK.

Source: Pubmed PMID: 18081025 (25/06/08)

Company Discovers Gene Sets Which Correlate to Multiple Sclerosis Ore Pharmaceuticals Inc. announced today that DioGenix, its molecular diagnostics subsidiary, has identified novel sets of genes that it believes will form the basis of a new assay to diagnose multiple sclerosis (MS), a disease of the central nervous system (CNS). DioGenix plans to refine these gene sets and further confirm their disease association before it begins to develop an effective commercial assay for diagnosing patients presenting with early symptoms of MS. The company is seeking strategic alternatives to fund DioGenixs product development efforts.

To discover these correlative gene sets, DioGenix scientists compared gene expression profiles from a genome-wide analysis of whole blood samples from MS patients, patients with alternative diseases which mimic MS and samples collected from normal donors. The scientists found statistically significant differences in gene expression between the groups, resulting in a novel gene set now covered by the Companys recent international patent filing. This work confirmed the results of an earlier DioGenix study, based on peripheral blood mononuclear cells, announced in an October 2007 press release.

This most recent study continues to provide encouraging evidence that we are on the right path to develop a clinically relevant diagnostic for MS, said Larry Tiffany, Chief Executive of DioGenix. A blood-based test that can diagnose MS would improve the quality of care for patients who currently must endure a lengthy, costly and invasive medical work-up, even in those cases where MS cannot be definitively diagnosed. This is the first phase of our MS program, as we build on our knowledgebase of MS disease biology and work to find markers that can monitor disease activity, identify sub-types of MS, and assess therapeutic activity.

MS is a chronic inflammatory disease that selectively destroys the myelin sheaths of neurons within the CNS, leading to loss of neurological function with unpredictable course and severity. In the United States alone, the disease affects approximately 400,000 persons and up to 25,000 new cases are diagnosed each year. Susceptibility to MS is determined by genetic and environmental factors that are not well understood. Current methods of diagnosis require a battery of expensive and, in many cases, invasive tests -- including lumbar puncture to access cerebral spinal fluid -- that often do not result in an accurate diagnosis.

Source: Ore Pharmaceuticals Inc. (10/06/08)

Study of islanders’ DNA to seek clues for a cure to Multiple Sclerosis A groundbreaking study of Scots' DNA is being launched to discover why the nation has the highest rates of multiple sclerosis in the world.

It is hoped the research, which involves scouring the genes of hundreds of people, will explain why patients contract the devastating disease and help the development of new treatments.

The populations of Orkney and Shetland are the focus of the investigation as MS is more common in the two island communities than anywhere else.

Residents who suffer from the illness will be asked to give blood, as well as locals who have no history of the disease, so scientists can compare the samples. They hope to untangle the genetic code which makes people vulnerable to MS and see if their blood responds differently to a virus which it is thought might trigger the illness.

Dr Jim Wilson, a population geneticist at Edinburgh University who is leading the study, said: "We hope to unravel the mystery as to why rates of MS are so high in Orkney, Shetland and Scotland and also to provide possible answers to patients who suffer the disease around the world."

Edinburgh University is already working on new drugs to combat the effects of MS at their dedicated research centre, which was set up using a grant from author JK Rowling. Dr Wilson is based in the university's MRC Human Genetics Unit and was researching the genetic traits which predispose people to heart disease on Orkney four years ago when he became interested in MS.

He said: "As we visited people on the doorstep everyone asked us why we were not studying MS. It is very high up in people's consciousness in Orkney because so many people have it. I felt an obligation to do it."

He has obtained a grant of £215,000 from the MS Society Scotland and is launching the project this month.

First, he will identify the exact number of patients with MS on the two island groups. A study from the 1970s suggests there are more than 60 sufferers on Orkney alone, but Dr Wilson believes the numbers may have increased.

He then intends to recruit every patient if possible and twice as many people of a similar age and background without MS for DNA testing. His team will analyse these samples to see if a variation of the gene DR15, which is already associated with the disease, is common on the islands. In addition they will search for previously undiscovered genetic variations.

Dr Wilson said: "We will be looking at more than 300,000 genetic markers using the most up-to-date technology available."

Finally, in collaboration with Aberdeen University, he plans to study how introducing elements of the virus which causes glandular fever affects white blood cells taken from both the patients and the controls, to see if there is a difference. There is reason to believe the Epstein-Barr virus may play a role in the onset of MS.

Dr Wilson, who is from Orkney, added: "There has not been a lot of immigration in Orkney so it is much easier to pick out the signal of a genetic effect from all the background noise."

Mark Hazelwood, director of the MS Society Scotland, said: "Scotland has the highest prevalence of multiple sclerosis in the world and we believe it must make a major contribution to international research efforts to understand it."

Dr Wilson wants to recruit MS patients born in Orkney and Shetland who have moved elsewhere for the research. They are asked to ring 0131 651 1643 or e-mail '); document.write(addy76240); document.write('<\/a>'); //-->\n This email address is being protected from spambots. You need JavaScript enabled to view it. " href="mailto: This email address is being protected from spambots. You need JavaScript enabled to view it. "> This email address is being protected from spambots. You need JavaScript enabled to view it. .

Source: The Herald © 2008 Newsquest (Herald & Times) Limited. (15/05/08)

Team work to discover genetic markers associated with Multiple Sclerosis (MS) and Autism

A team of prominent researchers at the University of Utah and Vanderbilt University are leveraging Utahs deep domain expertise in human genetic research and the Affymetrix Genome-Wide Human SNP Array 6.0 to discover genetic markers associated with Multiple Sclerosis (MS) and Autism.

Scientists led by Mark Leppert, Ph.D., professor and co-chair of the Department of Human Genetics at the University of Utah, are using the Affymetrix technology and LineaGens business domain expertise to generate and analyze genetic information from large multiplex Utah pedigrees, with corresponding decades worth of longitudinal clinical data. It is anticipated that the resulting information will provide researchers with greater understanding of these diseases, and enable more effective use of existing treatments and the development of novel molecular diagnostics and therapies.

MS is an unpredictable disease that attacks healthy tissue in the brain, spinal cord and optic nerves. Approximately 400,000 Americans have MS, and every week 200 more are diagnosed. The disease affects an estimated 2.5 million people around the world.

Autism Spectrum Disorders (ASDs) are characterized as a group of neurological disorders that lead to significant impairments in social interaction and communication, which typically last throughout an autistic persons lifetime. There is no known cure for Autism, and little is known about its causes. The Centers for Disease Control (CDC) estimates that as many as 1 in 150 children in the United States are diagnosed with an ASD.

We chose the Affymetrix SNP Array 6.0 because of its comprehensive genetic content, and its ability to analyze both SNP and copy number variations, said Dr. Leppert. We have a valuable and unique genetic population resource at the University of Utah and now we can cost-effectively conduct larger-scale studies to determine the genetic associations of common diseases like MS and Autism.

The Affymetrix arrays will be run in the lab of Shawn Levy, Ph.D., director of the Vanderbilt Microarray Shared Resource at Vanderbilt University Medical Center. We are excited to be working with the team at the University of Utah on this study, which will provide us with greater insight into the genetic causes of diseases like MS and Autism, which continue to baffle researchers after decades of research efforts, said Dr. Levy. The Affymetrix Array 6.0 is already delivering extremely high-quality results and were seeing unprecedented call rates.

The project is being managed and funded by LineaGen, a content-based biomarker discovery company focused on commercializing novel, patentable diagnostic tests that will lead to personalized healthcare regimens.

In seeking to further understand the genetic basis of MS and Autism, two of the more complex and challenging disorders which currently affect millions of people, it is essential that we work with the best research partners and genetic technologies available, said Michael Paul, Ph.D., president and CEO of LineaGen. This is why we have chosen to work with the University of Utah researchers uniquely qualified to analyze the Utah Population Database, and with Affymetrix and value-added partners such as Vanderbilt.

The most important metric of a whole-genome association study is the genetic power, said Kevin King, president of Affymetrix. The Affymetrix SNP Array 6.0 is the platform for genetic breakthroughs because it combines comprehensive genetic coverage and a cost-effective price per sample. Customers like the University of Utah, Vanderbilt and LineaGen are now able to perform higher-powered studies than ever before on diseases that affect millions of people around the world.

The Affymetrix SNP Array 6.0 is a single microarray that simultaneously measures more than 1.8 million markers for genetic variation. The array enables researchers to perform the most powerful whole-genome association and copy number studies ever by genotyping more markers across more individuals at a lower cost per sample. These higher-powered studies increase the probability of discovering genes associated with adverse drug response or complex diseases.

Source: Affymetrix Inc.(12/05/08)

Genetics of Multiple Sclerosis

Introduction

Evidence supports a genetic predisposition to MS. There is excess occurrence in Northern Europeans relative to indigenous populations from the same geographic location, a familial aggregation (MS is 20 to 40 times more common in first-degree relatives with rapid drop-off with degree of relatedness), and lack of excess of MS despite the shared environment in adopted relatives of patients with MS Based on the monozygotic twin studies, the genetic risk of MS can be estimated to be 25 to 30%. This drops to 3 to 5% in dizygotic twins, thereby supporting the “complex” susceptibility to MS with a significant environmental-physiological contribution to susceptibility risk.

From a practical perspective, the risk of MS in a first-degree relative of a patient with established MS, corrected for the population risk, is on average 2 to 4%. This varies with incidence-prevalence figures for the population at large from which the individual is drawn. In families with MS, fathers with MS have almost twice the possibility of passing MS to their children than mothers with MS. This excess inheritance from fathers with MS ultimately balances the expected disease excess in children of mothers with MS because women have almost a twofold greater incidence of MS than men; therefore, the greater chance of inheritance from fathers does not change the way a physician should counsel MS patients. Other studies suggested a possible increase in maternal risk of inheritance of MS, or no parent-of-origin effect at all. This parent-of-origin effect is independent of a child’s sex and cannot be explained by classical gender-dependent inheritance patterns such as X-linked or mitochondrial inheritance.

Clinical phenotypic heterogeneity in MS appears to have a genetic basis. Relative pairs with MS in family studies have greater similarity of clinical course than expected by chance. A large international study found affected sibling pairs to be concordant for age and year of disease onset and disease course, but not for disease severity. Interestingly, in the same study, affected parent-affected child concordance was only present for age of onset. Besides sharing a similar genetic background, affected sibling pairs also likely share a relatively similar environment when compared with their parents. Therefore, the results of this study highlight the contribution of having both a similar genetic and similar environmental background to develop a similar MS clinical phenotype. However, especially with the concordance in year of disease onset in affected sibling pairs, this study also suggests that exposure to a possible environmental factor(s) at a similar critical period may also be necessary to develop a similar clinical phenotype.

Genetic epidemiology studies are generally classified as hypothesis-independent whole genome studies (linkage or association) or hypothesis-driven candidate gene association studies. Each method has its drawbacks and strengths, but regardless of the method, a robust definition of the phenotype is necessary for the success of any genetic epidemiology study in complex disorders because different sets of genes and related pathways are potentially involved in different phenotypes. Some understanding of the concepts involved in each method is necessary to be able to interpret study results.

In disorders of complex etiology such as MS, where individual genetic contributions are expected to be common polymorphism effects, major limitations of hypothesis-independent whole genome studies relate to the sample size needed to study sufficient numbers of markers with adequate power to uncover small gene effects, especially when a correction for multiple comparisons is entertained.[1] Therefore, these studies are more likely to reveal false-negative results. However, a major advantage of these studies is the potential to discover novel pathways involved in disease etiopathogenesis that were not previously entertained.

Hypothesis-driven candidate gene association studies, on the other hand, require an intimate and scientifically well-supported understanding of the biology of the disease to identify reliable candidates to study. However, for most complex disorders, such candidates are not easily identified. The major advantage of these studies is the increased sensitivity and therefore the decreased sample size requirements, facilitating a dense study of the candidate region or the gene. These studies, however, are more prone to false-positive findings.

Ultimately, the study of genetic epidemiology of complex disorders requires a combined application of these methods, depending on the hypothesis under question.

A discussion of all the genetic studies in MS with controversial results is beyond the scope of this post. This review highlights some of the promising results from different regions and candidate genes of the human genome.

The HLA-DRB1*1501-DQB1*0602 haplotype on chromosome 6p21 is well accepted as a susceptibility locus for MS. This region was originally studied as a candidate for MS susceptibility in sporadic MS patient populations as part of the autoimmune hypothesis in MS, and later confirmed in hypothesis-independent genome-wide linkage studies in familial MS populations as part of large international efforts.[2,3] This association is further defined as being due to HLA-DRB1 rather than the DQ allele.[4,5] A study suggests that although the presence of HLA-DRB1*15 allele increases MS risk dominantly, HLA-DRB1*03 contributes to a smaller increased MS risk recessively. In addition, HLA-DRB1*14 decreases MS risk.[6] This study also confirms the previously defined lack of association between the HLA locus and disease course, disease severity, and age of onset in MS.[6]

There are other potential loci on chromosomes 5q33, 17q23, and 19p13 that show weak linkage with susceptibility to MS.[3] Another hypothesis-independent association study uniquely harnessing the greater haplotypic diversity and distinct patterns of linkage disequilibrium in patients of African descent identified an additional candidate locus on chromosome 1.[7] These loci await further confirmation of the likely candidate genes in these regions.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a costimulatory molecule involved in T-cell downregulation on engagement with B7. It is a key inhibitory molecule involved in the prevention of autoimmunity.[8] Polymorphisms of CTLA4 and the haplotypes formed between them have been associated with autoimmunity in general, although not driven by single polymorphism effects.[8] Several studies have shown an association with susceptibility to MS, although not always with the same markers, suggesting a haplotype effect rather than individual polymorphism effects.[9] Indeed, these effects in part may be driven via an interaction with the HLA-DRB1*15 allele.[10] Several other studies have failed to confirm these associations [10]. A recent study, however, suggests that CTLA4 polymorphisms are associated strongly in families with MS enriched for autoimmune diseases, but not in families without other autoimmune diseases.[11] This supports the notion that CTLA-4 acts as a common autoimmunity gateway and provokes further interest in this gene and chromosome region as a susceptibility marker for MS. Further work will be necessary to better understand the inherent contribution of CTLA4 polymorphisms to CTLA-4 function.

Interferon-gamma (IFNG) is a cytokine with key regulatory, immunomodulatory, and effector roles both in autoimmunity and MS. Polymorphisms of this regulator cytokine and the haplotypes formed between them are associated with MS susceptibility, likely in a gender-dependent fashion.[10,11] This association has not been confirmed in all studied populations.[12] Further confirmation and understanding of the inherent effects of the IFNG polymorphisms on expression will be necessary.

Apolipoprotein E (APOE) is associated with prevention of neurotoxicity and repair processes in a variety of neurological disorders.[13] APOE genotypes have been associated with disease severity in MS in some but not in all studies. APOE e3 and e4 alleles have been associated with neuronal loss measures on magnetic resonance spectroscopy.[14] The APOE e2 allele is associated with lesser disease severity in patients with familial MS,[15] and this association is present in women but not men with MS in population-based sporadic patients.[16] The APOE e4 allele has been associated with progressive disease in women and cognitive impairment in men with MS.[17] However, a meta-analysis failed to confirm these associations.[18] A study conducted in Greece suggests that APOE e4 allele may be associated with an unfavorable verbal learning score in MS patients.[19] Further studies are needed with more robust cognitive and imaging outcomes in MS before a conclusion regarding an association of APOE genotypes and MS can be reached.

Interleukin-7 receptor-a (IL7Ra/CD127) is a type I cytokine and is part of the cytokine receptor complex for the ligand IL7. IL7Ra-IL7 interaction is involved in proliferation of T and B lymphocytes with no redundancy. IL7Ra is located on chromosome 5p13, a region with some linkage of MS.[20] IL7Ra was associated with MS as a candidate gene,[21] followed by confirmation in two independent populations of patients with MS, one of which is a recent whole genomic study in MS.[21]

References

1-Weiss KM, Terwilliger JD. How many diseases does it take to map a gene with SNPs? Nat Genet 2000;26(2):151-157
2-GAMES; Transatlantic Multiple Sclerosis Genetics Cooperative. A meta-analysis of whole genome linkage screens in multiple sclerosis. J Neuroimmunol 2003;143(1-2):39-46
3-Sawcer S, Ban M, Maranian M, et al. A high-density screen for linkage in multiple sclerosis. Am J Hum Genet 2005;77:454-467
4-Oksenberg JR, Barcellos LF, Cree BA, et al. Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet 2004;74(1):160-167
5- Lincoln MR, Montpetit A, Cader MZ, et al. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nat Genet 2005;37(10):1108-1112
6-Barcellos LF, Sawcer S, Ramsay PP, et al. Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. Hum Mol Genet 2006;15(18):2813-2824
7-Reich D, Patterson N, De Jager PL, et al. A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility. Nat Genet 2005;37(10):1113-1118
8-Gough SC, Walker LS, Sansom DM. CTLA4 gene polymorphism and autoimmunity. Immunol Rev 2005;204: 102-115
9-Harbo HF, Celius EG, Vartdal F, Spurkland A. CTLA4 promoter and exon 1 dimorphisms in multiple sclerosis. Tissue Antigens 1999;53(1):106-110
10-Alizadeh M, Babron MC, Birebent B, et al. Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients. Ann Neurol 2003;54(1):119-122
11-Roxburgh RH, Sawcer S, Maranian M, et al. No evidence of a significant role for CTLA-4 in multiple sclerosis. J Neuroimmunol 2006;171(1-2):193-197
12-Dai Y, Masterman T, Huang WX, et al. Analysis of an interferon-gamma gene dinucleotide-repeat polymorphism in Nordic multiple sclerosis patients. Mult Scler 2001; 7(3):157-163
13-Gee JR, Keller JN. Astrocytes: regulation of brain homeostasis via apolipoprotein E. Int J Biochem Cell Biol 2005; 37(6):1145-1150
14-Enzinger C, Ropele S, Strasser-Fuchs S, et al. Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele [see comment]. Arch Neurol 2003;60(1):65-70
15-Schmidt S, Barcellos LF, DeSombre K, et al. Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis. Am J Hum Genet 2002;70(3):708-717
16-Kantarci OH, Hebrink DD, Achenbach SJ, et al. Association of APOE polymorphisms with disease severity in MS is limited to women [see comment]. Neurology 2004;62(5):811-814
17-Cocco E, Sotgiu A, Costa G, et al. HLA-DR, DQ and APOE genotypes and gender influence in Sardinian primary progressive MS. Neurology 2005;64(3):564-566
18-Burwick RM, Ramsay PP, Haines JL, et al. APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers. Neurology 2006;66(9):1373-1383
19-Koutsis G, Panas M, Giogkaraki E, et al. APOE epsilon4 is associated with impaired verbal learning in patients with MS. Neurology 2007;68(8):546-549
20-Ebers GC, Kukay K, Bulman DE, et al. A full genome search in multiple sclerosis [see comment]. Nat Genet 1996;13(4):472-476
21-Zhang Z, Duvefelt K, Svensson F, et al. Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun 2005;6(2):145-152

Source: Professor Yasser Metwally (28/04/08)

Gender-specific influence of the chromosome 16 chemokine gene cluster on the susceptibility to Multiple Sclerosis.

Macrophage-derived chemokine (MDC/CCL22) plays a role in Experimental Autoimmune Encephalomyelitis (EAE), the animal model of Multiple Sclerosis (MS). MDC/CCL22 gene is part of a chemokine cluster, which includes also thymus and Activation-Regulated Chemokine (TARC/CCL17).

The frequency of the C/T and C/A Single Nucleotide Polymorphisms (SNPs) in the promoter and coding sequence of CCL22 as well as the C/T SNP in the promoter of CCL17 were determined in 370 patients with Multiple Sclerosis (MS) compared with 380 controls. A trend towards a decreased allelic frequency of the A allele of the CCL22 C/A SNP as well as of the T allele of the CCL17 C/T SNP was found in patients compared with controls.

The frequency of the AT haplotype was significantly decreased in MS patients (P=0.017, OR: 0.49, CI: 0.28-0.87). Stratifying patients according to gender, the observed association was even more pronounced in male patients compared with male controls (P=0.004, OR=0.18, 95% CI: 0.06-0.50), whereas no significant differences were observed in females.

Therefore, the presence of the AT haplotype in chromosome 16 chemokine cluster is likely to confer a decreased risk of developing MS, particularly in males.

Galimberti D, Scalabrini D, Fenoglio C, De Riz M, Comi C, Venturelli E, Cortini F, Piola M, Leone M, Dianzani U, D'Alfonso S, Monaco F, Bresolin N, Scarpini E. Department of Neurological Sciences, "Dino Ferrari" Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza, 35, 20122, Milan, Italy. Source: Journal of the neurological sciences 2008 Apr 15;267(1-2):86-90 (19/03/08) A genome scan in a single pedigree with a high prevalence of multiple sclerosis.

BACKGROUND:
Multiple sclerosis (MS) is a disease that is widely believed to be autoimmune in nature. Genetic-epidemiological studies implicate susceptibility genes in the pathogenesis of MS, although non-MHC susceptibility linkages have been difficult to confirm. Insight into pathways that are intrinsic to other complex diseases has come from the genetic analysis of large, autosomal-dominant kindreds. Here, we present a genetic study of a large and unique kindred in which MS appears to follow an autosomal-dominant pattern of inheritance, with consistent penetrance in four generations.

METHODS:
Eighty-two individuals of this 370-member family were genotyped with 681 microsatellite markers spanning the genome, with an average spacing of 5.3 cM.

RESULTS:
Parametric linkage analysis was performed and no significant LOD score (LOD >3.3) was observed. For a rare dominant disease model with reduced penetrance, 99.6% of the genome was excluded at a LOD score <-1 and 96% at a LOD score <-2. The HLA-DRB1 candidate gene was also genotyped by allele-specific methods. In each instance where at least one parent was positive for HLA-DRB1*15, one or more HLA-DRB1*15 alleles were transmitted to the affected offspring (11/11). HLA-DRB1*15 was transmitted equally from both the familial and the married-in parents and therefore this locus does not appear to be an autosomal-dominant acting gene in this family but an important modifier of risk.

CONCLUSIONS:
These results further stress the importance of the HLA-DRB1*15-bearing haplotype in determining MS susceptibility. Furthermore, this study highlights the complexity of MS genetics, even in the presence of a single family, seemingly segregating MS as an autosomal-dominant trait.

Source: Pubmed PMID: 17550985 - J Neurol Neurosurg Psychiatry. 2008 Feb;79(2):158-62. (23/01/08)

Genetic loci linked to Type 1 Diabetes and Multiple Sclerosis families in Sardinia Abstract (provisional)

Background
The Mediterranean island of Sardinia has a strikingly high incidence of the autoimmune disorders Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). Furthermore, the two diseases tend to be co-inherited in the same individuals and in the same families. These observations suggest that some unknown autoimmunity variant with relevant effect size could be fairly common in this founder population and could be detected using linkage analysis.

Methods
To search for T1D and MS loci as well as any that predispose to both diseases, we performed a whole genome linkage scan, sequentially genotyping 593 microsatellite marker loci in 954 individuals distributed in 175 Sardinian families. In total, 413 patients were studied; 285 with T1D, 116 with MS and 12 with both disorders. Model-free linkage analysis was performed on the genotyped samples using the Kong and Cox logarithm of odds (LOD) score statistic.

Results
In T1D, aside from the HLA locus, we found four regions showing a lod-score greater than or equal to 1; 1p31.1, 6q26, 10q21.2 and 22q11.22. In MS we found three regions showing a lod-score greater than or equal to 1; 1q42.2, 18p11.21 and 20p12.3. In the combined T1D-MS scan for shared autoimmunity loci, four regions showed a LOD >1, including 6q26, 10q21.2, 20p12.3 and 22q11.22. When we typed more markers in these intervals we obtained suggestive evidence of linkage in the T1D scan at 10q21.2 (LOD = 2.1), in the MS scan at 1q42.2 (LOD = 2.5) and at 18p11.22 (LOD = 2.6). When all T1D and MS families were analysed jointly we obtained suggestive evidence in two regions: at 10q21.1 (LOD score = 2.3) and at 20p12.3 (LOD score = 2.5).

Conclusion
This suggestive evidence of linkage with T1D, MS and both diseases indicates critical chromosome intervals to be followed up in downstream association studies.

Maristella Pitzalis , Patrizia Zavattari , Raffaele Murru , Elisabetta Deidda , Magdalena Zoledziewska , Daniela Murru , Loredana Moi , Costantino Motzo , Valeria Orru , Gianna Costa , Elisabetta Solla , Elisabetta Fadda , Lucia Schirru , Maria Cristina Melis , Marina Lai , Cristina Mancosu , Stefania Tranquilli , Stefania Cuccu , Marcella Rolesu , Maria Antonietta Secci , Daniela Corongiu , Daniela Contu , Rosanna Lampis , Annalisa Nucaro , Gavino Pala , Adolfo Pacifico , Mario Maioli , Paola Frongia , Margherita Chessa , Rossella Ricciardi , Stanislao Lostia , Anna Maria Marinaro , Anna Franca Milia , Novella Landis , Maria Antonietta Zedda , Michael B. Whalen , Federico Santoni , Maria Giovanna Marrosu , Marcella Devoto and Francesco Cucca

Source: BMC Medical Genetics 2008, 9:3doi:10.1186/1471-2350-9-3 (21/01/08)

Genetic differences may help explain response to multiple sclerosis treatment

By comparing the DNA of patients with multiple sclerosis whose symptoms are reduced by interferon beta therapy to the DNA of those who continue to experience relapses, researchers may have identified important genetic differences between the two, according to an article posted online today that will appear in the March 2008 print issue of Archives of Neurology, one of the JAMA/Archives journals. These differences could eventually be used to help predict which treatments will help which patients.

Multiple sclerosis (MS) is a neurological disorder in which nerve fiber coatings degenerate, causing muscle weakness, spasms and partial or complete paralysis. A protein known as recombinant interferon beta is widely used to treat multiple sclerosis symptoms and possibly slow progression of the disease, according to background information in the article. “Despite interferon beta therapy, up to 50 percent of patients with MS continue to experience relapses and worsening disability,” the authors write. “In addition, adverse effects, such as flulike symptoms and depression, are common, leading many patients to discontinue therapy.”

Esther Byun, M.D., of the University of California, San Francisco, and colleagues of a multi-center international collaboration followed a group of 206 Southern European patients with relapsing-remitting MS—the most common type, in which patients experience periods of symptoms followed by periods of symptom-free remission—for two years after they began interferon beta therapy. Every three months, neurologists analyzed patients’ disability levels; throughout the study, 99 responded positively to interferon beta and 107 did not.

The researchers pooled the DNA of individuals in each group and used microarrays to identify, across the genome, genetic markers associated with the response to interferon beta. They identified the top 35 single nucleotide polymorphisms (SNPs), changes in a single base of DNA, that were candidates for further analysis. They then located these SNPs in each individual participant to see if the mutations apparent in responders differed from those in non-responders. After this analysis was complete, an additional 81 individuals with MS (44 responders and 35 non-responders) were included and the DNA of responders was again compared to that of non-responders.

Of the 35 candidate SNPs identified in the first screen, 18 were found to remain significantly associated with treatment response in the combined screen. Seven of the SNPs were located within genes, while the others were located in the space between genes. Some of the SNPs were located in genes previously linked to processes involved with MS, such as the growth and repair of nerve cells.

“The beneficial outcomes of interferon beta therapy for patients in the relapsing-remitting phase of MS have been clearly shown,” the authors write. “On the other hand, the effect of this treatment is partial, and a substantial amount of patients are not responders. Hence, in the absence of prognostic clinical, neuroradiological and/or immunological markers of response, the question remains who and when to treat when adverse effects, inconvenience and the cost of the drug are significant.”

The identification of genetic mutations that affect response to interferon provides important new information about how the drug functions in the body, bringing medicine one step closer to rational drug design and personalized medicine, the authors note. However, additional research will be needed to fully predict treatment outcomes based on DNA analysis.

Source: EurekaAlert! (15/01/08)

Gene appears to play a protective role in Multiple Sclerosis

New research announced this week has possibly found an association between certain genes and the severity of multiple sclerosis (MS).

The results of the study by Prof George Ebers, chair of Clinical Neurology at the Wellcome Trust Centre for Human Genetics, is to be published in the journal Proceedings of the National Academy of Sciences and represent a increase in the understanding of the probable role of genes in Multiple Sclerosis.

The study compared genes taken from people with severe MS who used wheelchairs within five years of being diagnosed and people who had no discernable disability 20 years after diagnosis.

It showed that a particular version of a gene called HLA-DRB1*01 was rare in people with severe MS and suggests it may play a protective role against the more severe progressive course that some people can experience with MS.

Dr Laura Bell, of the MS Society, said: “This interesting new study shows that particular genetic factors work to modify the progression of MS and provides insight into the processes which occur in MS development, however it is worth noting that MS is not directly inherited and there is no single gene that causes or prevents it. Environmental factors also play an important role in people’s susceptibility to developing MS.”

Source:  MS Society 10/12/07 World Experts Gather In Cambridge To Bid To Unravel Multiple Sclerosis Genes

International experts are gathering in Cambridge this week to plan the next step in their fight to unravel the genetics of multiple sclerosis (MS).

The Genetics of MS workshop, part-funded by the UK's MS Society and the USA's National MS Society, brings together 50 neurologists and scientists from across the EU, the United States and Australia.

A better understanding of the genes behind MS should improve chances of coming up with targeted and effective treatments.

Dr Stephen Sawcer, of Cambridge University, said: "The genes behind MS are more difficult to find than we thought and no individual group of researchers has enough power on their own.

"This workshop brings together a group of colleagues committed to bringing their expertise to bear to find out what they can about MS."

Simon Gillespie, chief executive of the MS Society, said: "The MS Society has doubled its research investment this year to £3million and we are very pleased that this means we can support this groundbreaking event. A better understanding of MS will be a major boost to everyone fighting to develop effective treatments."

The researchers gathering at Cambridge have joint access to data from more than 14,000 people with MS across the world and Dr Sawcer said they hoped access to this extensive pool of resources would better direct future treatments.

A similar approach bore fruit earlier this year when a core group of these researchers identified the first new MS genes in 30 years. This week will see the International MS Genetics Consortium (IMSGC) and the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) collaborative group joining forces to plan their next moves.

Dr Sawcer said: "We all tend to think that a specific gene causes a disease, but that's not the case in MS. In a complex disease like MS multiple genes, each exerting a modest individual effect, play only a role in influencing someone risk of developing the disease, and are not enough on their own to course the disease.

"There are probably around 100 genes involved in MS and you might need, say, 70 or so of the weaker forms of these genes for it to be possible to develop the condition. Understanding the genetics of MS will not lead to gene therapy or a diagnostic test for MS.

"Instead, what an understanding of MS will allow us to do is to focus research on the relevant parts of the immune system etc. You are far more likely to come up with an effective treatment if you have a clearer understanding of the disease, rather than relying on a process of trial and error."

Source: MS Society (09/11/07)

Scientists find new causes for neurodegeneration Diseases that cause neurons to break-down, such as Alzheimer's, Multiple Sclerosis and Creutzfeldt-Jakob disease (Mad Cow Disease), continue to be elusive to scientists and resistant to treatments.

A new finding from University of Michigan researchers demonstrates an unpredicted link between a virtually unknown signaling molecule and neuron health.

In a study released in PNAS, the journal of the National Academy of Sciences this week, graduate student, Yanling Zhang, postdoctoral fellow Sergey Zolov and Life Sciences Institute professor Lois Weisman connect the loss of this molecule to massive neurodegeneration in the brain.

The molecule PI(3,5)P2 is a lipid found in all cells at very low levels. Lipids are a group of small organic compounds. While the best studied lipids are fats, waxes and oils, PI3,5P2 is a member of a unique class of lipids that signal the cell to perform special tasks.

Weisman said it was surprising to find that PI(3,5)P2 plays a key role in the survival of nervous system cells.

"In mice, lowered levels of PI(3,5)P2 leads to profound neurodegeneration," said Weisman. "It suggests that we have a good place to look to find treatments for neurodegenerative diseases such as Alzheimer's."

Weisman, who is also professor of Cell & Developmental Biology at the U-M Medical School and her colleagues, began from clues that were hidden in a conserved genetic pathway in yeast (a pathway that has remained the same in yeast, plants and humans over evolutionary time). Studies in yeast showed that the enzyme that manufactures the lipid is governed by the FIG4 and VAC14 genes, which exist in yeast, mice and humans.

Working with two independently derived mouse models, Weisman's team and collaborators including graduate student Clement Chow and Professor Miriam Meisler of the Department of Human Genetics at the U-M Medical School, reached the same conclusions in a pair of important papers for neuroscience research.

Building on research from Meisler, a mouse geneticist, and Weisman, a yeast geneticist, the collaborators published a paper in Nature, July 5, 2007, showing that in mice, the FIG4 gene is required to maintain normal levels of the signaling lipid and to maintain a normal nervous system. Importantly, they found that human patients with a very minor defect in their FIG4 genes had serious neurological problems.

The signaling lipid PI(3,5)P2 (short for phosphatidylinositol 3,5-bisphosphate) is part of a communication cascade that senses changes outside the cell and promotes actions inside the cell to accommodate to the changes.

Weisman's team found that mice missing the VAC14 gene, which encodes a regulator of PI(3,5)P2 levels, suffer massive neurodegeneration that looks nearly identical to the neurodegeneration seen in the FIG4 mutant mice. In both cases the levels of PI(3,5)P2 are one half of the normal levels. The fact that both mice have half the normal levels of the lipid and also have the same neurodegenerative problems provides evidence that there is a direct link between the lipid and neuronal health.

The new findings indicate that when Vac14 is removed, the cell bodies of many of the neurons appear to be empty spaces and the brain takes on a spongiform appearance.

Source: University of Michigan (29/10/07)

Gene Logic Identifies Gene Expression Patterns Associated with Multiple Sclerosis in Blood Cells Company Is Collaborating with Accelerated Cure Project for Follow-On Studies Using Blood Samples.

Gene Logic Inc.announced today that it has identified gene expression patterns in white blood cells (WBC) that are statistically associated with multiple sclerosis (MS), a disease of the central nervous system (CNS). The company’s genomic analysis also identified gene patterns associated with two recently approved therapies for MS. To validate and extend its initial positive findings, Gene Logic is performing additional studies using blood samples from the repository of the Accelerated Cure Project for Multiple Sclerosis (ACP), a non-profit organization that has assembled the largest multi-disciplinary bio-bank for MS research.

MS is a chronic inflammatory disease that selectively destroys the myelin sheaths of neurons within the CNS, leading to loss of neurological function with unpredictable course and severity. The disease affects approximately 350,000 persons in the United States alone, and more than 25,000 new diagnoses are confirmed each year. Susceptibility to MS is determined by genetic and environmental factors that are not well understood, unfortunately requiring a battery of expensive and in many cases invasive tests to arrive at a diagnosis.

Gene Logic scientists evaluated the WBC samples using gene expression microarrays that enable comprehensive analysis of the human genome. They compared untreated MS samples with non-MS samples (both non-diseased and from other autoimmune diseases), as well as MS samples before and after treatment with Avonex® (beta-interferon) and Copaxone® (glatiramer acetate). Statistically significant gene expression differences between the groups were determined to identify gene sets.

These studies lay the foundation for several MS diagnostics that could have significant clinical applications, said Larry Tiffany, Senior Vice President and General Manager of Genomics at Gene Logic. A blood-based test that can definitively diagnose MS would clearly be of high value to physicians. A rule-out test demonstrating that a patient does not have MS would also be clinically useful, since it eliminates a lengthy, costly and often invasive medical work-up in many patients with symptoms similar to MS. Other potential applications of our comprehensive approach could be tests to monitor disease activity, identify sub-types of MS and functionally assess drug activity.

This is an exciting development for the MS community, said Art Mellor, founder of ACP. "Currently the diagnosis of MS takes an excruciatingly long period of time, often preventing patients from getting the early treatment they need to slow down its progress. This is an essential study and we are pleased to play a role in it."

Avonex® is a registered trademark of Biogen Idec.

Copaxone® is a registered trademark of Teva Pharmaceutical Industries Ltd.

About Gene Logic Molecular Diagnostics />

Gene Logic has developed proprietary comprehensive knowledgebases of human disease and response to therapy and capabilities to enable the discovery, validation and product development associated with commercially useful biomarkers. Past success has included prioritization of drug targets, identification of markers to predict toxicity and understand mechanisms of toxicity, and obtain insights into the efficacy of specific compounds. Gene Logic has recently begun to utilize these assets in combination with its in-depth clinical network to develop targeted diagnostic and prognostic marker sets with the ambition to develop these into assays which have broad ranging clinical utility.

Founded in 1994, the Genomics Division of Gene Logic is headquartered in Gaithersburg, Maryland. And it operates with additional research and development facilities in Cambridge, Massachusetts.

About Accelerated Cure Project for MS

The Accelerated Cure Project for Multiple Sclerosis, www.acceleratedcure.org, is a national nonprofit organization dedicated to curing Multiple Sclerosis (MS) by determining its causes. Accelerated Cure Project believes this effort can be accelerated by organizing the research process and encouraging collaboration between research organizations and clinicians. A "Cure Map" is currently being developed by the Accelerated Cure Project to establish what is known and what is not known about the causes of MS. From the Cure Map, Accelerated Cure Project will facilitate research most likely to reveal the causes of MS in the shortest time through a large-scale, multidisciplinary, MS Repository.

Source: Gene Logic Inc. (26/10/07)

Three Genomic Markers Correlate With Multiple Sclerosis: Presented at ANA Three gene variants have been found to correlate with susceptibility to multiple sclerosis, according to findings of the International Multiple Sclerosis Genetics Consortium (IMSGC) presented here at the 132nd Annual Meeting of the American Neurological Association (ANA).

Variants of interleukin 2RA, interleukin 7RA and CD58 were found to correlate with multiple sclerosis in a whole genome analysis that included about 4,500 participants. "The same finding has been reported in two other papers as well," noted Philip De Jager, MD, PhD, Assistant Professor, Neurology, Harvard Medical School, Boston, Massachusetts, United States, representing the IMSGC. "How these variants exert their effects is not known, and [will] become the subject of numerous investigations."

Dr. De Jager said that recent advances in genotyping technology and in our understanding of the structure of the human genome have enabled the execution of whole-genome-association scans for the first time. The IMSGC assayed approximately 70% of common genetic variation for their role in multiple sclerosis susceptibility.

First-degree relatives of patients with multiple sclerosis were screened to identify those at high risk. "These individuals could then be followed by a neurologist and undergo appropriate imaging. If genetic variants were identified, their pathways could be targeted using existing or future medications," Dr. De Jager speculated.

The screening sample consisted of 931 affected families, each containing a subject with multiple sclerosis and her biological parents. Half of participants in the study were from the United States, half from the United Kingdom.

Multiple sclerosis is twice as prevalent among populations of northern European descent than among other groups, with Scandinavia, Scotland and Ireland seeing the highest rates of the disease. Also, Sardinia has a higher rate of multiple sclerosis than other parts of Italy, said Dr. De Jager.

"Duplication of these same results in 10,000 subjects will be definitive," concluded Dr. De Jager. "The samples exist and the analysis should be completed in 2008."

Source: Presentation title: Whole Genome Association Screen in Multiple Sclerosis. Abstract 621 (15/10/07)

Secret codes of MS cracked Investigators have reported the biggest breakthrough in decades into the genetic drivers for multiple sclerosis, identifying two genes that each boost the risk of developing the disease by up to 30 per cent.

In MS, the immune system attacks myelin, the fatty sheath that protects the cells of the central nervous system, rather like plastic insulation protects electrical cables.

As a result, "short circuits" occur in the body's messaging system, because nerve signals get slowed or blocked. This leads to difficulties in movement and co-ordination, muscle weakness, cognitive impairment, slurred speech and vision problems.

Until now, investigations of the human genome have turned up only a cluster of variants of genes on Chromosome 6, in the so-called Major Histocompatibility Complex, which regulates the immune system.

But these genes were identified in the mid-1970s, leaving frustrated doctors to hunt for other culprits in the complex cascade of processes involved in MS. The new suspects play a role in guiding key immune cells, called T cells, which patrol the body for intruders.

They carry the name of interleukin-7 receptor alpha, or IL7R-alpha, located on Chromosome 5, and interleukin-2 receptor alpha (IL2R-alpha) on Chromosome 10, which has previously been associated with Type 1 diabetes. A single change in the genetic code in IL7-R, and two changes in IL2-R create the dangerous variants.

Each variant appears to boost the risk of MS by between 20 and 30 per cent.

"Our finding is very important, because the genetic factors that are already known to be associated with multiple sclerosis only explain less than half of the total genetic basis for the disease," said Simon Gregory, an Australian-born geneticist at Duke University in Durham, North Carolina, who took part in the IL7-R work.

The two studies, published simultaneously by Nature Genetics and the New England Journal of Medicine, were carried out by two consortiums of scientists, from the US and Cambridge University in Britain.

The genetic variants were unearthed thanks to a comparison of more than 20,000 samples of DNA, provided by patients diagnosed with MS and those without the disease, living in the US and Europe.

"People have been looking for genes involved in MS for 30 years," said David Hafler, a professor of neurology at Harvard Medical School, a lead author on the IL2-R study.

Source: The Australian Copyright 2007 News Limited. (29/07/07)

Publication Of Largest Ever Study Of Genetics Of Common Diseases The Wellcome Trust Case Control Consortium, the largest ever study of the genetics behind common diseases such as diabetes, rheumatoid arthritis and  coronary heart disease, has published its results in the journals Nature and Nature Genetics.

The £9 million study is one of the UK's largest and most successful academic collaborations to date. It has examined DNA samples from 17,000 people across the UK, bringing together 50 leading research groups and 200 scientists in the field of human genetics from dozens of UK institutions. Over two years, they have analysed almost 10 billion pieces of genetic information.

"Many of the most common diseases are very complex, part 'nature' and 'nurture', with genes interacting with our environment and lifestyles," says Professor Peter Donnelly, Chair of the Consortium, who is based at the University of Oxford. "By identifying the genes underlying these conditions, our study should enable scientists to understand better how disease occurs, which people are most at risk and, in time, to produce more effective, more personalised treatments."

The study has substantially increased the number of genes known to play a role in the development of some of our most common diseases. Many of these genes that have been found are in areas of the genome not previously thought to have been related to the diseases.

"Just a few years ago it would have been thought wildly optimistic that it would be possible in the near future to study a thousand genetic variants in each of a thousand people," says Dr Mark Walport, Director of the Wellcome Trust, the UK's largest medical research charity, which funded the study. "What has been achieved in this research is the analysis of half a million genetic variants in each of seventeen thousand individuals, with the discovery of more than ten genes that predispose to common diseases.

"This research shows that it is possible to analyse human variation in health and disease on an enormous scale. It shows the importance of studies such as the UK Biobank, which is seeking half a million volunteers aged between 40 and 69, with the aim of understanding the links between health, the environment and genetic variation. New preventive strategies and new treatments depend on a detailed understanding of the genetic, behavioural and environmental factors that conspire to cause disease."

Amongst the most significant new findings are four chromosome regions containing genes that can predispose to type 1 diabetes and three new genes for Crohn's disease (a type of inflammatory bowel disease). For the first time, the researchers have found a gene linking these two autoimmune diseases, known as PTPN2.

The study has also confirmed the importance of a process known as autophagy in the development of Crohn's disease. Autophagy, or "self eating", is responsible for clearing unwanted material, such as bacteria, from within cells. The may be key to the interaction of gut bacteria in health and in inflammatory bowel disease and could have clinical significance in the future.

"The link between type 1 diabetes and Crohn's disease is one of the most exciting findings to come out of the Consortium," says Professor John Todd from the University of Cambridge, who led the study into type 1 diabetes. "It is a promising avenue for us to understand how the two diseases occur. The pathways that lead to Crohn's disease are increasingly well understood and we hope that progress in treating Crohn's disease may give us clues on how to treat type 1 diabetes in the future."

Research from the Consortium has already played a major part in identifying the clearest genetic link yet to obesity and three new genes linked to type 2 diabetes, published in April in advance of the main study. It has found independently a major gene region on chromosome 9 identified by independent studies on coronary heart disease.

Researchers analysed DNA samples taken from people in the UK - 2,000 patients for each disease and 3,000 control samples - to identify common genetic variations for seven major diseases. These are bipolar disorder, Crohn's disease, coronary heart disease, hypertension, rheumatoid arthritis and type 1 and type 2 diabetes. For each disease, the researchers will study larger population samples to confirm their results.

Although the human genome is made up of more than three billion sub-units of DNA, called nucleotides (or bases), most of these show little in the way of differences between individuals. A substantial part of the variation in DNA sequence between individuals is due to single-nucleotide polymorphisms (differences), also known as SNPs. There are approximately 8 million common SNPs in European populations. Fortunately, because SNPs that lie close together on chromosomes often tell quite similar stories, researchers in the Consortium were able to explore this variation through analysing a subset of these SNPs (in fact approximately 500,000).

"Human genetics has a chequered history of irreproducible results, but this landmark collaboration of scientists in Britain has shown conclusively that the new approach of analysing a large subset of genetic variants in large samples of patients and healthy individuals works," says Professor Donnelly. "We are now able to effectively scan most of the common variation in the human genome to look for variants associated with diseases. This approach will undoubtedly herald major advances in how we understand and tackle disease in the future."

Further analysis as part of the Consortium will be looking at tuberculosis (TB), breast cancer, autoimmune thyroid disease, multiple sclerosis and ankylosing spondylitis. The results are expected later this year.

Source: Medical News Today © 2007 MediLexicon International Ltd (10/06/07)

International Collaboration Uncovers Genetic Commonalities

The Federation of Clinical Immunology Societies (FOCIS) has taken on the role of connecting multiple disease specific, genetic consortia under the FOCIS Network of Consortia in an effort to uncover the genetic basis of autoimmunity.

The Network, spearheaded by FOCIS President, David Hafler, MD, Harvard University and Stephen Rich, PhD, Wake Forest University, has recently completed genome wide association scans revealing novel candidate genes that may provide important insights into disease pathogenesis and therapeutic targets.

The results will be presented for the first time on June 11 at the Federation's Annual Meeting (FOCIS 2007) in San Diego.

Francis Collins, MD, PhD of the National Human Genome Research Institute will present a cross-section of data from ongoing genome wide association scans in autoimmune disease -- inflammatory bowel disease (IBD), juvenile idiopathic arthritis (JIA), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and type 1 diabetes (T1D). In addition, the Wellcome Trust Case Control Consortium (WTCCC) will present a series of disease-oriented genome wide association scans using a common control group.

"Scientists that once worked in disease-specific silos are uniting to create a catalogue of common genetic variations that will enable scientists to unravel underlying causes of autoimmune diseases," said Stephen Rich. "New data across diseases is showing great commonality, identifying potential targets that work across autoimmune diseases," he added.

The work of the initial phase of the genome wide association scans for autoimmunity will be presented at FOCIS 2007 Network of Consortia session. 

For more information visit http://www.focisnet.org/.

Source: Federation of Clinical Immunology Societies (10/06/07)

Studies in the area of multiple sclerosis genetics reported from Tehran University of Medical Sciences, Department of Immunology

Profile of cytokine gene polymorphisms in Iranian multiple sclerosis patients.

"Cytokine gene polymorphisms have been extensively studied in association with different diseases. The role of cytokine gene polymorphisms in multiple sclerosis (MS), as a chronic immune-mediated neurodegenerative disease, has been previously reported. DNA samples were collected from 44 patients with relapsing-remitting multiple sclerosis (RRMS) and 140 unrelated healthy subjects," scientists writing in the journal Multiple Sclerosis report.

"All participants in this study were matched for ethnicity. Cytokine gene SNPs were determined using the PCR-SSP method. We found no significant differences between MS patients and controls in most of the studied cytokine genes. Remarkable results were obtained for IL-2 GG-330 genotype (p=0.06), IL-6 C-174 allele (p=0.06), CG and GG genotypes (p <0.001), and GG (p=0.02) and CG (p <0.001) haplotypes, and TNF-alpha A-238 allele (p <0.001), GG (p=0.003) and GA (p <0.001) haplotypes," wrote A. Amirzargar and colleagues, Tehran University of Medical Sciences, Department of Immunology.

The researchers concluded: "These results suggest that polymorphic variations of these pro-inflammatory cytokines play an important role in susceptibility to MS."

Amirzargar and colleagues published their study in Multiple Sclerosis (Profile of cytokine gene polymorphisms in Iranian multiple sclerosis patients. Multiple Sclerosis, 2007;13(2):253-5).

Source: Therapeutics Daily ©2005 PharmaLive.com(15/05/07)

Researchers discover gene crucial for nerve cell insulation Researchers funded by the National Institutes of Health have discovered how a defect in a single master gene disrupts the process by which several genes interact to create myelin, a fatty coating that covers nerve cells and increases the speed and reliability of their electrical signals.

The discovery has implications for understanding disorders of myelin production. These disorders can affect the peripheral nervous system—the nerves outside the brain and spine. These disorders are known collectively as peripheral neuropathies. Peripheral neuropathies can result in numbness, weakness, pain, and impaired movement. They include one of the most common genetically inherited disorders, Charcot-Marie-Tooth disease, which causes progressive muscle weakening.

The myelin sheath that surrounds a nerve cell is analogous to the insulating material that coats an electrical cord or wire, keeping nerve impulses from dissipating, allowing them to travel farther and faster along the length of the nerve cell.

The researchers discovered how a defect in just one copy of the gene, known as early growth response gene 2 (EGR2) affects the normal copy of the gene as well as the functioning of other genes, resulting in peripheral neuropathy.

"The researchers have deciphered a key sequence essential to the assembly of myelin," said Duane Alexander, M.D., Director of the NICHD, the NIH institute that funded the study. "Their discovery will provide important insight into the origins of disorders affecting myelin production."

The study appears in the online version of Molecular and Cellular Biology.

John Svaren, Ph.D., an associate professor in the Department of Comparative Bioscience at the University of Wisconsin–Madison's School of Veterinary Medicine, worked with colleagues Scott E. LeBlanc, and Rebecca M. Ward, to conduct the study. Dr. Svaren is an affiliate of NICHD-funded mental retardation and developmental disabilities research center at the Waisman Center at the University of Wisconsin.

Until this discovery, researchers did not fully understand the complex genetic process that enables Schwann cells, found in the peripheral nervous system, to coat nerves with myelin.

The Newly Discovered Role of EGR2

During this study, the scientists found that EGR2 produces a protein that activates several other genes necessary for myelin production. Some of these genes contain the information needed to make peripheral myelin protein 22 (PMP-22) and myelin protein zero (MPZ). MPZ is the most abundant protein in myelin in the peripheral nervous system.

The overproduction or underproduction of the proteins PMP22 and MPZ account for the majority of inherited peripheral neuropathies, Dr. Svaren said.

Ultimately, the sequence of activating genes "switches on" the Schwann cell, which wraps the nerve axon, the arm-like projection that conveys nerve impulses, in a myelin sheath.

The scientists' research also resolved a long-standing mystery surrounding why a single mutant copy of the EGR2 gene disrupts the functioning of the normal EGR2 gene, leading to a disorder of the nervous system.

In many genetic conditions, the unaffected copy of an affected gene continues to produce its protein. However, the researchers found that the mutant EGR2 copy interferes with the interaction between the normal EGR2 gene and another myelin gene, SOX10, as the two try to work together to produce the myelin protein MPZ.

Therapeutic Potential

By understanding the process which creates myelin, researchers may now be able to investigate new therapies for disorders affecting myelin.

"Our research has uncovered a whole new mechanism for regulating myelin genes," said Dr. Svaren. "Our hope is to exploit this knowledge so that we can adjust the levels of myelin genes such as PMP22 and MPZ, and thereby create an effective treatment for myelin diseases."

Understanding the process by which nerve cells are myelinated also could be applied to other disorders as well, Dr. Svaren said. Diabetic neuropathy, which results in a loss of feeling in the extremities, also is thought to involve myelin production.

Dr. Svaren added that it is possible that the current study's findings about myelin production in the peripheral nervous system could lead to greater understanding of how myelination takes place in the central nervous system (the brain and spinal cord). Myelination in the central nervous system is not well understood. Multiple sclerosis, a degenerative muscular disorder that can be fatal, results from the destruction of myelin in the central nervous system.

Source: NIH/National Institute of Child Health and Human Development (16/04/07)

Gene Behind Autoimmune Diseases Identified by Researchers A report in the March 22 issue of the New England Journal of Medicine reveals that a pinpointed region of chromosome 17, a gene named NALP1, could be a new target of treatment for autoimmune diseases. This is a particularly exciting discovery because NALP1, a gene known to control part of the immune system that serves to alert the body to viral and bacterial attacks, has not previously been specifically implicated in autoimmune diseases, affirms the American Autoimmune Related Diseases Association (AARDA), a national nonprofit patient advocacy organisation. The discovery was the result of collaboration between St. George University of London, the University of Colorado at Denver and Health Sciences Center (UCDHSC), and the Barbara Davis Center for Childhood Disorders.

Why does the body choose the misdirected path of attacking itself, in an autoimmune process, when it sets out to eliminate invaders, such as bacteria or viruses, thus resulting in autoimmune diseases--for example, lupus, multiple sclerosis, rheumatoid arthritis, vitiligo, thyroiditis (Graves', Hashimoto's), juvenile (type 1) diabetes, or any one of the more than 100 such diseases?

The findings of this latest research study, which followed 656 persons from 114 extended families in the United States and the United Kingdom who had multiple autoimmune diseases, give the researchers a clue as to why the immune system attacks one of the body's own tissues. "If the sensor NALP1 is overreactive, it could trigger a response to the wrong stimulus," said Professor Dorothy Bennett, Professor of Cell Biology at St. George's University of London, investigator for the UK arm of the study. She added, "We hope to study exactly how this works and to learn even more from the other genes that we are working to identify."

Lead investigator Dr. Richard Spritz, director of the Human Medical Genetics Program at UCDHSC, was quoted as saying, "Since NALP1 appears to be part of our body's early-warning system for viral or bacterial attack, this gives us ideas about how to try to discover the environmental triggers of these diseases." Dr. Spritz said, "This finding may also open up new approaches to treatment, possibly for many different autoimmune diseases."

Dr. Peter Gregerson, director of the Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research in Manhasset, NY, calls the study "provocative." He said, "It raises the issue of whether this gene might be involved in more common disorders." He also commented that this research is a good example of "a successful, family-based approach to gene identification and an example of how new genes identified that way can raise new connections among different diseases."

It has been estimated that 50 million Americans are affected by autoimmune diseases which rank among the top ten causes of death in women. Recognition of the family connection, as alluded to by Dr. Gregerson, is important because the ability to develop an autoimmune disease is determined by a dominant genetic trait that is very common (20 percent of the population) and may present in families as different autoimmune diseases within the same family. It is important for families with members who have autoimmune diseases to mention this fact when another member of the family is experiencing medical problems that are difficult to diagnose. "Autoimmune diseases are often difficult to diagnose; however, a family history of autoimmune disease is a major clue" said Virginia Ladd, President of the American Autoimmune Related Diseases Association.

Source: Newswise © 2007 Newswise. All Rights Reserved. (27/03/07)

Computer Key Unlocks Heritable Disorders Danish and Belgian researchers have found a computer key that maps genes underlying heritable disorders, such as breast cancer, multiple sclerosis, and Alzheimer’s disease. These results will possibly ease the discovery of new medicines and improve treatment in various disorders.

The results – which are published in the current issue of Nature Biotechnology – show that genes important for the development of diseases like Alzheimer’s follow the same cellular rules as genes involved in fundamentally different disorders, such as heart disorders, multiple sclerosis, breast cancer, and Type 2 diabetes.

”Many disorders manifest themselves in fundamentally different ways, but the new surprising discovery is that the underlying genes play together after the same rules. Our results show that the genes that trigger diseases, regardless of the type of disease in question, are social team players who cooperate according to highly specific rules. These rules have now been mapped, and we have pointed at hundreds of new genes that are likely to be involved in disorders including multiple sclerosis, Parkinson, heart disorders, and diabetes”, says Kasper Lage from Technical University of Denmark, who is the project coordinator on this work.

Heritable disorders will be easier to interpret for clinicians using the new results. Furthermore, the identification of new genes likely to be involved in disorders will help patients with defects in these genes. For example, if you are a high risk carrier of a gene that underlies a disease such as Type 2 diabetes, physicians could prevent or delay the manifestations of the disease by dietary guidance early in life.

”This is a crucial breakthrough for our understanding of heritable disorders, and a breakthrough for systems biology as a research strategy in the field genetics and disease”, says Søren Brunak leader of Center for Biological Sequence analysis at the Technical University of Denmark. ”We work with genes and proteins, but also with clinical literature describing the characteristics of different disorders. Then we let the computer integrate all of these data, and extract the pattern”, he adds.

The results are the product of a collaboration between the Center for Biological Sequence analysis, the Wilhelm Johannsen Center for Functional Genomics, Steno Diabetes Center in Denmark, and the SymBioSys Center for Computational Systems Biology, Katholieke Universiteit Leuven in Belgium.

Source: Technical University of Denmark (08/03/07)

New multiple sclerosis genetics study findings reported from Griffith University, Genomics Research Center

Investigators publish new data in the report "Allelic variation investigation of the estrogen receptor within an Australian multiple sclerosis population."

According to a study from Southport, Australia, "Multiple Sclerosis (MS) is a central nervous system (CNS) chronic inflammatory demyelinating disease leading to various neurological disabilities. The disorder is more prevalent for women with a ratio of 3:2 female to male. To investigate variation within the estrogen receptor 1 (ESR1) polymorphism gene in an Australian MS case-control population using two intragenic restriction fragment length polymorphisms; the G594A located in exon 8 detected with the BtgI restriction enzyme and T938C located in intron 1, detected with PvuII."

"One hundred and ten Australian MS patients were studied, with patients classified clinically as Relapsing Remitting MS (RR-MS), Secondary Progressive MS (SP-MS) or Primary Progressive MS (PP-MS). Also, 110 age, sex and ethnicity matched controls were investigated as a comparative group. No significant difference in the allelic distribution frequency was found between the case and control groups for the ESR1 PvuII (p=0.50) and Btg1 (p=0.45) marker," wrote L. Tajouri and colleagues, Griffith University, Genomics Research Centre.

The researchers concluded: "Our results do not support a role for these two ESR1 markers in multiple sclerosis susceptibility, however other markers within ESR1 should not be excluded for potential involvement in the disorder."

Tajouri and colleagues published the results of their research in the Journal of the Neurological Sciences (Allelic variation investigation of the estrogen receptor within an Australian multiple sclerosis population. Journal of the Neurological Sciences, 2007;252(1):9-12).

The publisher of the Journal of the Neurological Sciences can be contacted at: Elsevier Science BV, PO Box 211, 1000 AE Amsterdam, Netherlands.

Source: Therapeutics Daily ©2007 PharmaLive.com (25/02/07)

When the Body Attacks Itself Scientists link 30 genes to multiple sclerosis and other autoimmune diseases.

The immune system is what keeps most people's bodies healthy and free of disease, but for as many as 23 million Americans, it is a cause of disease, too. In autoimmune disorders, the system goes haywire, mistaking the body's own tissues for foreign invaders and destroying them. Drugs for these conditions, which include type 1 diabetes, multiple sclerosis and lupus, have been elusive. But on Sunday, scientists are reporting in the journal Nature that they have found a set of 30 genes that go awry in autoimmune disorders—and that could be potential targets for cures. NEWSWEEK's Mary Carmichael spoke with two of the discoverers, Richard Young, a biologist at the Massachusetts Institute of Technology's Whitehead Institute, and Alexander Marson, an M.D./Ph.D. student in Young's lab.

Excerpts:

NEWSWEEK: What do these 30 genes normally do in a healthy person's body?

Richard Young: There was a very, very important discovery made about a decade ago, which was that a specialised class of "regulatory T cells" was controlling the immune system's arms of attack. Now, the million-dollar question is why this wonderful system that keeps you healthy might turn against you and begin to attack your own body. And it turns out that in these autoimmune disorders, there are genetic defects in the regulatory T cells, which would otherwise be a check on the rest of the immune system.

These regulatory T cells can't keep the system in line, and it starts attacking things it shouldn't?

Alexander Marson: Yes. In mice, if you remove all the regulatory T cells, what you see is a massive, multiorgan autoimmune disease. In some common human autoimmune disorders, like multiple sclerosis, there's not a total lack of these cells, but there's a subtler dysfunction. The regulatory T cells are present, but they don't work as well at turning off the other immune cells and preventing them from attacking the body.

What exactly is wrong with the genes in these regulatory T cells? What are they doing that they shouldn't be doing?

Young: In autoimmune disorders, most of these genes are less active than they normally would be. What Alex and his colleagues discovered is that this turns the regulatory T cells' activities down, so they're not as aggressive or powerful as they normally would be. Now, it was only three years ago that scientists discovered the "brain" of the regulatory T cells, or the gene that tells them how to do their job. This is a gene called Foxp3.

So Foxp3 is the immune system's big boss, and the 30 genes you've found inside the regulatory T cells are the middle managers?

Young: Right. Until now, it was not known exactly how Foxp3 was giving these T cells directions—which genes it was controlling in order to do that.

And these are the 30 genes, the ones that aren't following the proper directions. So you think this dysfunction is the basis not just for one disorder, but a whole host of autoimmune diseases?

Marson: Yes, regulatory T cells appear to be key in preventing type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease, as well as autoimmune thyroid disorders. Dysregulation of the genes controlling those cells could contribute to a wide range of autoimmune conditions.

That's a huge number of people—the pharmaceutical industry must be very excited about this discovery?

Young: The imperative in the pharmaceutical industry, when you're thinking about investing nearly a billion dollars in a program, is to have deep knowledge of the molecular pathways you're going to be focused on. There's this sea of noise that's hard to get through when you're looking for drug targets, unless you have a very small group of genes to look at. Here, we have that—we have the opportunity to take many, many, many autoimmune diseases and search more quickly because we've narrowed down the genes that are involved. Considering what drives the industry, this gives them a real leg up on developing cures.

What if you narrowed it down further? Could a drug for all of these disorders be aimed at Foxp3, the master controller of these 30 genes?

Young: It's an option. If you find some secret souce that will modify Foxp3's activities and you've shown that this is critical to a broad spectrum of disorders, that's going to be a great thing. Let's say for the sake of speculation that in one of these diseases, Foxp3 itself is not working at adequate levels or is slightly defective. That would make it a single target we could go after and see if we could tune it up. On the other hand, it could turn out—as it usually does—that life's more complex than that. For each one of the diseases, there may be some subset of the 30 target genes that aren't working right, and we'd have to use another, more specific approach in each disorder.

Marson: One of the key next steps is to take each of these 30 genes and figure out what they're doing within the T cells. There's evidence that they play important roles, but the molecular underpinning of that is really still unknown. The other thing will be to look for chemicals that mimic the function of Foxp3. There may be some that are already known, but hopefully there will be more to be discovered in the future.

Could you also manipulate these genes in healthy people to suppress the immune system if you needed to, the way doctors do now in organ transplantations?

Young: Sure. In the same vein that you can imagine the loss of function of these genes, you can think of situations where you'd like to turn down the immune response, like in transplantation. There are already drugs that do that, of course, but the best evidence we have so far is that those drugs are working in a different way, on different genes than the ones we've discovered. Then again, sometimes if you discover new genes and then you go and test what the known drugs are doing, you're often surprised that they're doing multiple things and are involved in pathways you didn't anticipate.

Marson: One of the major drugs that's used to suppress the immune system now is cyclosporin, which inhibits a protein called NFAT. We and others have evidence that Foxp3 is also inhibiting that protein.

Young: Many of these genes are operating together with others, collaborating in the control of regulatory T-cell function. They're like drinking buddies. So it may turn out that the connection is a whole lot closer than we've imagined.

Source: MSNBC Newsweek© 2007 Newsweek, Inc. (21/01/07)

MS hits North Africans harder than Europeans Multiple sclerosis (MS) follows a more severe course in North Africans than Europeans, a new study from France shows.

MS is fairly common in France, which is considered to be a relatively high-risk country. It is much more common in France, striking more than 100 people for every 100,000 citizens, than in North African countries, where the prevalence is 15 per 100,000 people, Dr. Marc Debouverie of the Central Hospital in Nancy and colleagues note.

The variable prevalence of MS throughout the world is thought to be related to the effects of genetic make-up, environmental factors, or both, the researchers add in the January issue of Neurology.

France has many North African residents, and due a high volume of immigration in the 1950, it also has a large number of second-generation North Africans.

The researchers compared how MS manifested itself in North Africans who emigrated to France, evaluating 211 North Africans and 2,945 Europeans.

The disease struck the North Africans at an earlier age, about 30 years old compared to about age 33 for Europeans, the researchers found. The most severe form of MS, known as primary progressive disease, was more common among North Africans, with 15.6% having this type of MS, compared twin 11.7% of Europeans.

North Africans were also less likely to have a complete recovery from their first bout with the illness, had a shorter average time before relapses; had more relapses in the first five years of having the disease; and became disabled more quickly. For example, North Africans started requiring a cane for walking an average of 10 years earlier than Europeans.

MS also developed earlier in French-born North Africans earlier than those who emigrated to the country, which was the only difference between the two groups in terms of the disease course.

Given that all of the study participants shared the same environment, the findings suggest that the differences in MS course between North Africans and Europeans are genetically based, Debouverie and colleagues conclude.

SOURCE: Neurology, (13/01/07)

Study confirms increased MS rates The recently released findings of a new study appear to confirm long-held suspicions that local communities Morrison and Paw Paw have higher-than-average rates of multiple sclerosis - particularly among women.

The study found Morrison in particular had 21 confirmed cases of MS - all of them women - which represents about 218 cases for every 100,000 people. That's about 2 1/2 times the average diagnosis rate, which is about 85 diagnoses for every 100,000 people, according to a national survey.

Multiple sclerosis or MS is a disease that affects the brain and spinal cord resulting in loss of muscle control, vision, balance, sensation or thinking ability, according to the medical Web site WebMD. The exact cause of the disease is unknown.

Studies typically have found about two or three women are diagnosed with MS for every man with the disease, but in the communities studied locally, the rate was much higher - 11 women diagnosed for every man.

"It boils down to about one out of every 300 women in the areas that we studied (have multiple sclerosis)," said Joel Cowen, principal investigator at Health Systems Research of the University of Illinois College of Medicine at Rockford. "The key message I think is the Morrison area is predisposed (to MS). It has this big female excess. That is a really high level, probably highest in any of the known literature."

The study was able to verify three cases of MS for Paw Paw, representing more than 2 1/2 times the average rate because of Paw Paw's small population. Lewiston also had a higher rate, but Savanna and DePue were not elevated, the study found.

Although the study confirmed long held rumours of high rates of MS for Morrison, Paw Paw and Lewistown, the researchers could not find any environmental factors to explain why the numbers were elevated, Cowen said.

"We really don't have an answer to say why it is so high," Cowen said. "We can really just say it is so high and that women with a northern European background in northern Illinois should be on the lookout for this."

That particular ancestry appears to be a factor in all the communities studied. Of the 37 individuals diagnosed with multiple sclerosis, all 37 had a northern European background, Cowen said. Morrison is know to have strong Dutch and German roots.

"I think women need to be aware in this area that being of northern European ancestry is a risk factor," Cowen said.

Genetics are also thought to play a part in the disease. Eleven of the study participants had a blood relative with MS. Because small towns "may have many related persons," genetic predisposition could also be one of the factors for the elevated levels of the disease, the study found.

The results for Morrison mirror a 1993 study also done by the University of Illinois College of Medicine in Rockford at the behest of the Whiteside County Health Department.

In the 1993 study, 23 people said they had multiple sclerosis in the Morrison ZIP code. That study was different because the findings were based on self-designation, meaning the 23 people simply told the researchers they had MS; the diagnosis was not verified medically, Cowen said.

This time around participants agreed to have their medical records reviewed by an expert at Texas Tech University who verified whether participants actually had MS, Cowen said.

Verification is important because MS was once a "disease of exclusion," meaning doctors would sometimes diagnose patients with the disease simply because the patient's symptoms didn't match any other illness. Cowen said Monday that the study identified several people in the five communities who were either misdiagnosed with MS or whose diagnoses couldn't be confirmed.

The researchers in the current study also looked at the background of all the study participants, searching for commonalties in past living locations, jobs or other factors. Cowen said he'd heard local rumours blaming water supplies or industrial pollution for the high rate of MS, but his study found no evidence supporting any particular environmental cause.

The study - one of five conducted in the United States to better understand MS and ALS, also known as Lou Gehrig's Disease - was funded with a grant given in October 2002 by the Agency for Toxic Substances and Disease Registry. Cowen recently sent the completed study's data to the agency, where it will be compiled with the four other studies in hopes of better understanding the disease.

While the results may not have been a breakthrough in discovering an environmental cause or trigger for MS, Cowen said the results were unique in finding a generally high rate in several of the towns, especially among women.

Eventually, Cowen hopes the medical community creates a national database for MS, similar to the current database for cancer victims. That way researchers could better study the disease, Cowen said. He said he'd would also like to sponsor a future conference on MS in Rockford.

Source: Sauk Valley.com Copyright © 2006 Sauk Valley Newspapers - All Rights Reserved (15/11/06)

Scientist outlines genetics, MS link As a teenager, Dessa Sadovnick screened Disney movies in an empty classroom to raise money for multiple sclerosis research. Now the University of British Columbia geneticist spends her time studying the disease.

"My involvement with MS has gone back since before I was born, and it seemed like a natural evolution to just go on and study MS as I got older."

Ms. Sadovnick spoke of the connection between genetics and multiple sclerosis at the MS research luncheon Thursday in Halifax. She has been involved with the Multiple Sclerosis Society of Canada since a friend, Evelyn Opal, co-founded the organisation.

Multiple sclerosis recurs more often in families than in the general population, her study found. If a sibling has multiple sclerosis, you are 15 to 25 times more likely to develop it yourself.

Identical twins have identical DNA. There is a 34 per cent chance both twins will develop multiple sclerosis, according to the study. But there is only a 5.2 per cent chance that both fraternal twins — who only share half their DNA — will get the disease.

"It really indicates that genetics are important," Ms. Sadovnick said.

Atlantic Canada has one of the highest rates of multiple sclerosis in Canada, according to research published by the MS Society. Genetics could play a role in this, Ms. Sadovnick said.

"There are so many people who are interrelated in the Maritimes that probably this increased risk is because people are sharing genetic material," she said.

But the genes involved in causing MS have not yet been identified. It is difficult to identify specific genes because they interact with environmental factors as well, the geneticist said.

Ms. Sadovnick compared the search for genetic causes to a road map. "With gene mapping the big general maps have been done (but) we still have a lot more work to do before we can pinpoint the exact genes involved."

The research that Ms. Sadovnick is doing is getting us closer to curing the 5,000 Atlantic Canadians living with multiple sclerosis, said Sarah Cowan, from the society’s Atlantic division.

Source: TheChronicleHerald.ca © 2006 The Halifax Herald Limited (27/10/06)

'Angel and devil’ genes hold the key to treatment for MS Multiple Sclerosis symptoms can be affected by a pair of "angel and devil" genes that fight to make a patient healthy or ill, researchers have found. The discovery could help scientists find ways of tackling the potentially devastating disease.

Scotland has the highest proportion of people with MS  in the world - about 10,500 have the condition.

One of the genes thought to be responsible for MS is called DR2b. Now scientists have learned that it is the "evil twin" in a pair of DR2 genes. MS is a life-long condition with symptoms including pain, muscle problems, impaired mental function, and poor vision. In severe cases it can lead to disabling loss of limb movement.

MS symptoms are caused by a rogue immune response, where the body attacks its own central nervous system.

The researchers found that DR2b exacerbates these symptoms, but its partner gene DR2a tries to dampen them and counteract DR2b's effects.

Professor Lars Fugger, from the Medical Research Council's Human Immunology Unit at Oxford University, who led the study, said: "The DR2b gene clearly tells the immune system to go hard into battle against the body's own tissue, so it starts to work in a way that actually damages the person.

"For this reason, natural selection has eliminated the gene on its own, but allowed it to be inherited only when it is accompanied by another gene (DR2a) which tempers its effect."

Professor Fugger's team bred mice with different combinations of DR2 genes in order to investigate their effects.

The scientists, whose findings appear today in the journal Nature, hope exploiting DR2a's control mechanism may lead to treatments for MS.

Research into other autoimmune diseases may benefit. Professor Fugger said: "This study is not only relevant to understand how genes interact in MS, but also in diabetes, rheumatoid arthritis and psoriasis, which are all autoimmune diseases."

Simon Gillespie, chief executive of the Multiple Sclerosis Society, said: "This is a very interesting finding which adds another piece to our understanding of the MS puzzle . . . We share the researchers' hope that it could eventually play a part in helping to treat this very variable and unpredictable condition."

Source: The Herald Copyright © 2006 Newsquest (Herald & Times) Limited. All Rights Reserved (28/09/06)

International team analyses human genetic variation in key immune region In-depth analysis will enable scientists to identify genetic risk factors for common immune diseases.

An international group of researchers today unveiled a detailed map of human genetic variation within the major histocompatibility complex (MHC), the most important region of the human genome encoding the human response to infection, autoimmune disease and organ transplantation. The work represents a milestone in the analysis of genetic variability for this fundamental immune region and lays the scientific foundation for future efforts aimed at uncovering the genetic roots of immune-related diseases. The findings of this international team, which includes scientists from the Montreal Heart Institute (MHI), the Université de Montréal (UdeM), the Broad Institute of MIT and Harvard and several other research institutions, appear in the September 24 advance online edition of Nature Genetics.

"This new map will be a key resource for researchers to use to find genes affecting health, disease, and responses to medications," said senior author Dr. John D. Rioux, PhD, who is associate professor of medicine at the UdeM and at the MHI where he works as a researcher and director of the Laboratory in Genetics and Genomic Medicine of Inflammation, visiting scientist of the Broad Institute of MIT and Harvard, and holder of the Canada Research Chair in Genetics and Genomic Medicine of Inflammation. "It will provide the information necessary to design powerful studies to identify the genetic risk factors located within the MHC."

The MHC -- specifically, the genes that comprise it -- is associated with more diseases than any other region of the human genome. This includes common diseases such as atherosclerosis, arthritis, diabetes, HIV, lupus, multiple sclerosis and Crohn's disease. However, pinpointing the specific changes that are causative in these diseases has been complicated by two factors: the extremely high degree of genetic diversity that exists in the MHC among different individuals and the tendency for multiple genetic differences in this region to be inherited together in groups called "haplotypes."

To characterise the haplotype patterns of the MHC, the researchers analysed the variability in its DNA sequence in more than 350 individuals from diverse geographic regions, including Africa, Europe, China and Japan. Specifically, the researchers "read" ~7,500 single-letter changes in the genetic code called single nucleotide polymorphisms (SNPs) together with short segments of DNA sequence from a set of highly variable genes within the MHC, called "HLA genes." These genes form a distinctive fingerprint that is recognised by an individual's immune system to distinguish foreign tissues from "self" tissues and the genes' DNA sequences are frequently analysed (a process called "HLA typing") in patients who receive organ transplants or suffer from autoimmune disease.

Importantly, the researchers' data and analyses, which are made available online to the entire scientific community, provide the tools needed to begin the initial efforts toward identifying genetic risk factors in the MHC for common immune-mediated diseases. Such endeavors, involving researchers at the Montreal Heart Institute, the University of California, San Francisco and the Broad Institute of MIT and Harvard, are now underway for several immune system diseases.

In addition, the results offer insights into the evolutionary history of the MHC region -- its early origins and the evolutionary forces that have helped to shape it over time. The findings also suggest that analysing select SNPs within the HLA genes may offer a more economical alternative for characterising the most common genetic variants in the region than standard HLA typing methods.

Nearly three-quarters of the DNA samples that the scientists analysed had been previously examined as part of the International Haplotype Map ("HapMap") Project, a worldwide scientific collaboration to catalogue human genetic variation on a genome-wide scale. The latest findings, particularly the analyses of the HLA gene region, provide new and complementary information that can be integrated with data from the recently completed HapMap Project as well as other genomic efforts, to provide a comprehensive view of genetic variability in the human MHC.

Data access

Data from the project will be made publicly available at the following website:

http://www.inflammgen.org

de Bakker P.I.W. et al. (2006) A high resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nature Genetics doi:10.1038/ng1885

A complete list of the study's authors and their affiliations:

Paul I.W. de Bakker(1,2,16), Gil McVean(3,16), Pardis C. Sabeti(1,16), Marcos M. Miretti(4,16), Todd Green(1), Jonathan Marchini(3), Xiayi Ke(5), Alienke J. Monsuur(6), Pamela Whittaker(4), Marcos Delgado(4), Jonathan Morrison(4), Angela Richardson(1), Emily C. Walsh(1), Xiaojiang Gao(7), Luana Galver(8), John Hart(9), David A. Hafler(10), Margaret Pericak-Vance(9), John A. Todd(11), Mark J. Daly(1,2), John Trowsdale(12), Cisca Wijmenga(6), Tim J. Vyse(13), Stephan Beck(4), Sarah Shaw Murray(8), Mary Carrington(7), Simon Gregory(9), Panos Deloukas(4), John D. Rioux(1,14,15)

Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA

Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA

Department of Statistics, University of Oxford, Oxford, United Kingdom

Wellcome Trust Sanger Institute, Hinxton, United Kingdom

Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom

Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, The Netherlands

Laboratory of Genomic Diversity, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, USA

Illumina, Inc., San Diego, California, USA

Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA

Brigham and Women's Hospital, Department of Neurology, Boston, Massachusetts, USA

Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge

Cambridge Institute for Medical Research, Addensbrookes Hospital, Hills Road, Cambridge, UK

Imperial College of London, London, United Kingdom

Université de Montréal, Department of Medicine, Montréal, Québec, Canada

Montreal Heart Institute, Montréal, Québec, Canada

About the Montreal Heart Institute
Founded in 1954, the Montreal Heart Institute constantly aims for the highest standards of excellence in the cardiovascular field through its leadership in prevention, ultra-specialized care, training of professionals, clinical and fundamental research, and assessment of new technologies. It is affiliated with the Université de Montréal and its clinical outcomes are among the best in the world. The MHI Research Centre officially came into existence in 1976 and has made enormous strides since its creation. Today, there are approximately 450 employees, students and researchers at the MHI Research Center. The MHI's outstanding feature is the balance it achieves between basic research, clinical research and clinical care. Its prime focus areas of research are vascular diseases, myocardial function and electrophysiology. Genomics (including pharmacogenomics), biomarkers and preventive cardiology are other areas of focus.

About the Université de Montréal
Founded in 1878, the Université de Montréal today has 13 faculties and together with its two affiliated schools, HEC Montréal and École Polytechnique, constitutes the largest centre of higher education and research in Québec, the second largest in Canada, and one of the major centres in North America. It brings together 2,400 professors and researchers, accommodates nearly 55,000 students, offers some 650 programs at all academic levels, and awards about 3,000 masters and doctorate diplomas each year.

About the Broad Institute of MIT and Harvard
The Broad Institute of MIT and Harvard was founded in 2003 to bring the power of genomics to biomedicine. It pursues this mission by empowering creative scientists to construct new and robust tools for genomic medicine, to make them accessible to the global scientific community, and to apply them to the understanding and treatment of disease.

The Institute is a research collaboration that involves faculty, professional staff and students from throughout the MIT and Harvard academic and medical communities. It is jointly governed by the two universities.

Organised around Scientific Programs and Scientific Platforms, the unique structure of the Broad Institute enables scientists to collaborate on transformative projects across many scientific and medical disciplines.

Source: The University of Montreal (25/09/06)

North-east Scotland has highest MS rate in the world The North-east of Scotland has the highest number people suffering from MS - in the world.

Multiple Sclerosis is the most common disease to effect the central nervous system and is more prevalent among people living in this area than anywhere else on the planet.

It is believed that MS is a genetic disease and it affects 1 in 700 people living in the North-east of Scotland and there is no recognised cure.

It is caused when a person's spinal tissue becomes inflamed and the messages coming to and from the brain become disrupted and even cut off completely. The most common ages in which MS symptoms appear are between 25-30 for women and 30-35 for men with women twice as likely to suffer from the disease. But the unpredictable nature of the disease means that the age of diagnosis can spread in either direction with people both in their teens and in their 60s being identified as having MS.

Colin Webster, president of the Scottish Association of Multiple Sclerosis, which run 10 therapy centres across the country, said: "The spinal cord is like a telephone line connecting messages to and from the brain.

"When a person has Multiple Sclerosis the messages become distorted and in the worse cases the messages can be completely cut off. For example if the messages between a persons brain and their legs are cut off then the legs will stop working."

It is not just a persons legs that are affected - the debilitating illness can work its way up the body and effect other bodily functions such as arms and speech and it is still unknown what causes the disease.

Mr Webster said: "After 200 years the disease is still not very well understood. There have been suggestions that the body's central nervous system in effect turns against itself.

"It is almost certainly caused by a genetic predisposition and is more prevalent in some parts of the country than others.

"There are theories that MS is helped by warmer climates but that is by no means the case and there are people with MS in countries where the climate is hot."

The disease can present itself in different ways but is often characterised by spells of attack and remission. According to Mr Webster one of the major problems with tackling MS is the unpredictable nature of the disease.

He explained: "There is no ability or test to predict what will happen in individual cases.

Frankly there is no successful available anti-inflammatories and often there is a slow progression of the disease."

Source : The Buchan Observer Copyright © 2006 Archant Regional. All rights reserved. (23/08/06)

Multiple Sclerosis in genetically susceptible twins is augmented by the northern environment A new study of twins suggests that living farther north of the equator significantly increases risk of developing Multiple Sclerosis (MS) among those with genetic susceptibility due to some environmental factor.

By following more than 700 pairs of twins diagnosed with MS, researchers from the Keck School of Medicine of the University of Southern California found that people born in the north tended to come to physicians for diagnosis slightly earlier than those born farther south, and that the tendency for identical twins to both be diagnosed was greater in those born in the north.

The concordance (both twins being diagnosed with MS) among identical twin pairs born in the north was nearly twice as high as among those born elsewhere (18.6 % vs. 9.5%). There was significantly less concordance among fraternal twins. The results were published in the in the July issue of Annals of Neurology.

Locations categorised as "northern" included Canada or states at or above 42 degrees north, including Alaska, Oregon, Washington, Idaho, Montana, Nebraska, North Dakota, South Dakota, Wyoming, Michigan, Minnesota, Wisconsin, Connecticut, Maine, Massachusetts, New Hampshire, New York, Rhode Island and Vermont.

Twins were divided into two categories, either monozygotic (identical twins with the same genetic makeup, coming from one egg) or dizygotic (fraternal twins, coming from two separate eggs). An effect that is seen more commonly in the monozygotic twins suggests a heavier role is being played by genes.

"We've known that MS is more common the farther away from the equator you get," says Thomas Mack, professor of preventive medicine at the Keck School of Medicine of USC and lead author of the study. "By looking at the number of times this occurs in twins – both identical and fraternal twins – we could see whether it was just a matter of latitude or if there is something else. This study suggests there's more concordance among identical twins, which means there is some environmental exposure and it is interacting with the genes."

If environment alone was responsible for the increased incidence of both members of the twin pair getting MS, there would be similarly high concordance among fraternal twins. The study did not suggest that, however, showing instead that both identical twins were far more likely to get the disease than both fraternal twins.

In fact, despite clear evidence of a much higher incidence of MS among women, the study found high concordance in both male and female identical twins, implying that mechanisms of inheritance are probably identical by sex. In other words, genetic susceptibility trumps the traditional bias against MS in most males.

Northern residence also contributed significantly to earlier onset of the disease. The researchers suggest that an early onset in the North could represent an early environmental deficit in protection, such as by less opportunity for early exposure to the sun, or for unknown reasons to an unrecognised causal factor, such as a virus. "It may even be that exposure to the sun interrupts whatever effect a virus has," Mack says.

The study was supported by the Multiple Sclerosis Society, the National Institute of Neurological Disease and Stroke (a part of the NIH), and the National Cancer Institute.

Talat Islam, W. James Gauderman, Wendy Cozen, Ann S. Hamilton, Margaret E. Burnett and Thomas M. Mack, "Differential Twin Concordance for Multiple Sclerosis by Latitude of Birthplace." Annals of Neurology Volume 60, Issue 1, Date: July 2006, Pages: 56-64

Source: University of Southern California (10/08/06)

RheoGene Grants Ichor Medical Systems a Commercial License to Develop a Regulated Gene Therapy for Multiple Sclerosis Using the RheoSwitch® Therapeutic System RheoGene, Inc., announced today that it has granted a commercial license to Ichor Medical Systems for use of its RheoSwitch® Therapeutic System (RTS) in combination with Ichor Medical Systems’ proprietary TriGrid™ Delivery System electroporation technology to develop a gene therapy product for multiple sclerosis. The agreement also grants Ichor an option to use RTS in two additional indications.

RheoGene’s RheoSwitch® Therapeutic System (RTS) is a safe and effective means to regulate both the level (dose) and timing of therapeutic gene expression using an orally administered Activator Drug. In addition to therapeutic dosing, RTS will provide the patient with an unprecedented safety mechanism that allows gene expression to be completely shut off in the event of adverse side effects, simply through withdrawal of the Activator Drug.

Electroporation uses the propagation of electric fields to greatly increase the uptake of DNA drugs by cells. Although this technique has been widely used in research laboratories, the development of clinical products based on this technology has been hindered by the lack of a simple, reliable, and effective means for procedure administration. Ichor’s TriGrid™ Delivery System integrates several patented technologies, into a simple handheld device that is designed to enable safe, efficient, and reproducible DNA drug delivery with minimal operator training.

Under this agreement, Ichor has the option to develop an exclusive, Ichor-proprietary formulation for the RTS Activator Drug now under development by RheoGene, or Ichor may opt to have RheoGene develop an Ichor-exclusive Activator Drug for its proprietary gene therapy products.

Ichor has also granted an option for RheoGene to license Ichor’s TriGrid™ Delivery System to develop proprietary therapeutics.

“We are excited about the opportunity to work with Ichor, a leading developer of electroporation-mediated human gene therapy,” said Thomas Tillett, RheoGene President and CEO. “The combination of Ichor’s proprietary DNA delivery technology and RheoGene’s RTS gene regulation system will enable highly safe, effective and controlled delivery of therapeutic genes to patients with serious unmet medical needs. This collaboration provides RheoGene with a near-term opportunity to introduce the RTS system into the clinic.”

“We anticipate that regulation of gene expression with RheoGene’s RTS system will greatly enhance the safety and functionality of a number of our DNA drug candidates,” said Drew Hannaman, Vice President -- Research and Development of Ichor Medical Systems. “We also expect that the combination of Ichor and RheoGene technologies will accelerate clinical testing and subsequent commercialization of DNA-based protein delivery for a broad range of indications.”

Source: RheoGene Press release (10/02/06)

Nutra Pharma Reports Discovery of New Gene Involved in MS

Nutra Pharma Corp., a biotechnology holding company that owns rights to intellectual property related to the development of drugs for HIV and Multiple Sclerosis (MS) has announced that their continuing microarray studies have identified a new gene involved in the disease process of Multiple Sclerosis. Although the gene and some of its functions are already known, this is the first evidence of involvement with the disease state of MS. The research also provides evidence that RPI-78M modulates the expression of this gene in laboratory assays. RPI-78M is the lead drug candidate of Nutra Pharma's holding, ReceptoPharm, Inc. and is being studied in preclinical assays for its efficacy in treating MS.

Eno Research and Development, Inc. (ERDI) was contracted by Nutra Pharma to analyze samples of immune cells and brain lesion material from MS patients, with and without the addition of RPI-78M. They measured the changes in gene expression that occurred with treatment. Statistical evaluation of the data revealed more than sixty genes with significant changes in expression as a result of exposure to RPI-78M. In analyzing the affected genes, at least thirty of them may have a specific role in the progression of the disease and symptoms of MS.

"While RPI-78M alters the regulation of genes known to be involved with MS, we are especially excited by the modulation of this gene previously unassociated with MS at all. Work to further characterize the involvement of this gene in the disease progression of MS is ongoing," commented James Flowers, President and Chief Scientific Officer of Eno Research and Development, Inc. (ERDI). "The data from this study suggests that RPI-78M may aid the patient in reversing some of the damage caused by MS. It is notable that if these results were replicated in the patient population it may greatly reduce the severity of the disease," he concluded.

There has been a great deal of interest surrounding research in Multiple Sclerosis therapies. There are currently four drugs on the market for the treatment of the disease. A fifth drug, Tysabri, was voluntarily pulled from the marketplace in February by the drug's manufacturers, Biogen-Idec and Elan.

"We are working diligently with ERDI to bring this information to the scientific community," commented Rik J Deitsch, Chief Executive Officer of Nutra Pharma. "We expect to present the data at related conferences and to seek publication of the finished work. We are also seeking to patent this gene as a potential new target for MS therapies. If we are successful, the patent may provide revenues through partnerships and licensing. These studies, when coupled with the positive results in the animal models, create substantial evidence of the drug's effects against MS," he added.

About Nutra Pharma Corp.

Nutra Pharma Corp. is a biopharmaceutical company specializing in the acquisition, licensing and commercialization of pharmaceutical products and technologies for the management of neurological disorders, cancer, autoimmune and infectious diseases. Nutra Pharma Corp. through its subsidiaries carries out basic drug discovery research and clinical development and also seeks strategic licensing partnerships to reduce the risks associated with the drug development process. The Company's holding, ReceptoPharm, Inc, is developing technologies for the development of drugs for HIV and Multiple Sclerosis (MS). The Company's other holding Infectech, Inc., is engaged in the research and development of diagnostic test kits designed to be used for the rapid identification of infectious diseases such as Tuberculosis (TB) and Mycobacterium avium-intracellulare (MAI). Nutra Pharma continues to identify and acquire intellectual property and companies in the biotechnology arena. www.nutrapharma.com

About ReceptoPharm, Inc.

ReceptoPharm is a bio-pharmaceutical company developing proprietary therapeutic proteins for the treatment of several chronic, life-threatening viral, auto-immune and neuro-degenerative disorders, specifically including Rabies, HIV, and Myasthenia gravis (MG). www.receptopharm.com

About Eno Research and Development, Inc.

Eno Research and Development, Inc. (ERDI) is a full-service contract research organization located in Hillsborough, North Carolina, near Research Triangle Park. ERDI offers a wide range of pre-clinical development services to pharmaceutical, biotechnology, medical device, animal health and nutraceutical companies. The scientific staff of ERDI possess expertise in biotechnology, pharmacology, tumor biology, synthetic and analytical chemistry, in silico modeling of drug interaction/binding and rational drug design, as well as microarray technology and bioinformatics. With this expertise, ERDI can offer services ranging from lead discovery through New Drug Applications. www.enoresearch.com

Source: Nutra Pharma Corp (19/12/05)

© Multiple Sclerosis Resource Centre

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