August 3, 2007

Immune system gene linked to MS: study

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Jonathan Haines, Ph.D., and colleagues have identified a gene variant that increases risk for multiple sclerosis. (photo by Neil Brake)

Immune system gene linked to MS: study

The genes that contribute to multiple sclerosis (MS) have been defying identification for more than 30 years.

Only a single gene locus has been found to contribute strongly to MS; no other genes — of the more than 100 that have been associated with the disease — have reached consensus.

Now, a multi-center team provides solid genetic and functional evidence for a gene linked to MS. The Multiple Sclerosis Genetics Group, which includes investigators at Vanderbilt University, reports this week in Nature Genetics that the interleukin 7 receptor (IL7R) alpha chain gene is associated with MS. The finding offers fresh opportunities for investigating the molecular causes of MS and seeking new therapeutic options.

“The genetics of MS has been very difficult to crack,” said Jonathan Haines, Ph.D., director of the Center for Human Genetics Research at Vanderbilt and senior author of the paper. “This is the first MS-associated gene outside of the major histocompatibility complex that has been confirmed in multiple populations. It gives us insight into a new signaling pathway that we can now hopefully exploit to identify targets for treatment.”

MS is an unpredictable, chronic inflammatory disease of the central nervous system. It destroys the myelin sheaths around nerve cells, causing a range of symptoms including visual problems, muscle weakness and disability. MS is thought to result from a complex interplay of genetics and environmental triggers and affects about 350,000 individuals in the United States.

The MS Genetics 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,” said Margaret Pericak-Vance, Ph.D., director of the Miami Institute for Human Genomics at the University of Miami and a senior member of the MS Genetics Group. “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.”

Using the genomic convergence approach, the investigators selected three candidate genes, which they analyzed in a group of 760 Caucasian families that included 1,055 MS patients. They identified a significant association with MS susceptibility for a single variation in one of the three genes — the IL7R alpha chain.

Candidate genes have had a spotty history when tested beyond the initial study.

“This has been the big knock on candidate gene studies in complex disease: they almost always fail to replicate,” Haines said.

The IL7R-alpha gene passed the reproducibility test. The investigators confirmed its association with MS risk in three additional independent populations: 438 MS patients and 479 controls in the United States; 1,338 MS patients and their parents in northern Europe; and 1,077 MS patients and 2,725 unrelated controls, also in Northern Europe.

“The combined datasets include several thousand affected individuals, which gave us the statistical power to find a genetic variation with a moderate effect,” Haines said.

The IL7R-alpha variant increases an individual's risk for MS by about 20 percent.

“It probably explains only a small proportion of MS risk,” Haines said, “but what's really exciting is that it's outside of the major histocompatibility complex and gives us a new functional pathway to examine.”

IL7R participates in immune system responses and in T cell development. Haines and colleagues showed that the genetic variant associated with MS risk changes the processing (alternative splicing) of the receptor. This change increases the amount of soluble IL7R and decreases the amount of membrane-bound IL7R — the “active” form of the receptor that mediates IL7 signaling in immune system cells. The investigators propose that carriers of the MS risk allele produce less membrane-bound IL7R, which in turn affects IL7 function.

The International Multiple Sclerosis Genetics Consortium, which includes Haines' team, also confirmed the link between IL7R and MS. The consortium used a “whole genome association” approach to scan the entire human genome for variants associated with MS. The group reports in the New England Journal of Medicine that the IL7R and another previously suspected gene, IL2R, are associated with increased risk for MS.

Jacob McCauley, Ph.D., a post-doctoral fellow in Haines' lab was a key factor in the success of the NEJM work. McCauley, who is supported by a National Multiple Sclerosis Society post-doctoral grant, performed most of the statistical analysis on more than 500,000 genetic markers.

“It is exciting to be part of one of the first whole genome association scans and to experience the success we've achieved with this project,” McCauley said.

The MS Genetics Group also includes Stephen Hauser, M.D., and colleagues at the University of California at San Francisco. The group collaborated with scientists in the United Kingdom and Belgium to confirm the IL7R association. The research was supported by the National Institutes of Health and the National Multiple Sclerosis Society.