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Multiple Sclerosis Gene Uncovered After 30-year Search

For the first time in more than three decades, a multi-center team of researchers has uncovered a gene linked to multiple sclerosis (MS) that could pave the way for future research and treatment options.

Nature Genetics and the New England Journal of Medicine are publishing two separate but related studies today that report the most significant MS genetic breakthrough since the 1970s and only the second MS genetic risk factor confirmed through research.

Researchers from Vanderbilt University, the University of Miami, the University of California at San Francisco, Duke University, and the University of Cambridge participated in both studies.

The Nature Genetics paper “provides solid genetic and functional evidence that the interleukin 7 receptor (IL7R) alpha chain gene is associated with MS” said co-corresponding author Jonathan Haines, Ph.D., director of the Center for Human Genetics Research at Vanderbilt. This specific genetic variation can increase an individual’s risk of getting MS by about 20 percent, he said.

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“The genetics of MS has been very difficult to crack,” said Haines, also senior corresponding author of the NEJM paper that further confirmed this result.

“This is the first MS-associated gene outside of the major histocompatibility complex (MHC) that has been confirmed in multiple populations.” said co-corresponding author Margaret Pericak-Vance, Ph.D., director of the Miami Institute for Human Genomics at the Miami Miller School of Medicine and co-leader of the project while working at Duke University.

These researchers collective 15 years of research, supported by the National Institutes of Health, focused on the analysis of more than 10,000 DNA samples from MS patients and unaffected individuals.

The group used a powerful technique called “genomic convergence” that integrates multiple sources and types of evidence to implicate candidate genes in complex diseases.

“We took a very systematic approach, we looked at multiple lines of evidence that would give us the best chances of successfully identifying a gene that was truly involved in MS susceptibility,” said Pericak-Vance.

"We have identified the first gene to be genetically and functionally implicated in the development of MS in the last 30 years,” said Simon Gregory, Ph.D., assistant professor at the Center for Human Genetics, Duke University, and first author of the paper.

“Now we need to identify the reasons why this gene, which plays an intimate part in the normal functioning of the immune system, may be involved in this complex and devastating disease. IL7R will ultimately be only one of a number of genes involved in the development of MS."

The MS Group collaborated with scientists in the United Kingdom and Belgium to confirm the IL7R association. No other genes – of the more than 100 that have been associated with the disease – have reached consensus.

The International Multiple Sclerosis Genetics Consortium (IMSGC) in the NEJM paper confirmed these findings by using a technique called “whole genome association” that scans the entire human genome for variants that associated with MS. This effort also identified a statistical association with the IL7R gene, along with another previously suspected gene, IL2R.

Between 1972 and 1975 researchers found that a variant of the human leukocyte antigen (HLA-DRB1) increases the likelihood of getting the disease up to fourfold. When combined with IL7R, these two genes increase the risk of getting MS by fivefold, researchers said.

MS is an unpredictable, chronic inflammatory disease of the central nervous system that affects about 350,000 individuals in the United States. It is thought to result from a complex interplay of genetics and environmental triggers. Symptoms include visual problems, muscle weakness and disability.

| newswise
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