A large-scale genomic study has uncovered new genetic variations associated with multiple sclerosis, findings that suggest a possible link between multiple sclerosis and other autoimmune diseases.
The study, led by an international consortium of clinical scientists and genomics experts, is the first comprehensive study investigating the genetic basis of multiple sclerosis.

Findings are published in the New England Journal of Medicine.

The study, which analyzed genomic information from 12,360 people, confirmed that immune system genes are altered in people diagnosed with multiple sclerosis, and pointed to potential mechanisms of the disease.

The researchers gathered 931 sets of DNA samples from patients with multiple sclerosis and their parents.
They analyzed single nucleotide polymorphisms ( SNPs ), that is, small differences in DNA sequence that represent the most common genetic variations between individuals, and looked for variations that were more commonly inherited by people with multiple sclerosis, compared to samples from people without the disease.
To double-check the findings, they performed a second analysis of other sets of families, individual cases of multiple sclerosis, and a control group. In the end, all the samples were combined for a final analysis of more than 12,000 subjects.

The only genetic link for multiple sclerosis previously identified using other techniques is in the major histocompatibility complex ( MHC ), a large cluster of genes responsible for many immune functions, including preventing the body’s immune cells from attacking its own tissues. This analysis confirmed that link but went further to find other variants in genetic regions that are more common in people with multiple sclerosis.

One of the regions contains a gene called the IL-2 receptor, which has also been linked to two other autoimmune diseases: type 1 diabetes and autoimmune thyroid disease.

Another region harbors a gene called the IL-7 receptor, which helps to control the activity of a class of immune cells called regulatory T cells. Two papers appearing simultaneously in Nature Genetics confirm this finding, and explore how the change in the IL-7 receptor affects the immune system. “ I believe that this receptor and its interaction with regulatory T cells will now become a major focus of research on multiple sclerosis,” says Stephen Hauser, at University of California San Francisco ( UCSF ), and another author on the paper.

This latest paper is among a series of recent whole-genome association studies that have begun to uncover the genetic basis of complex diseases like diabetes, schizophrenia, and coronary artery disease. Unlike diseases caused by a mutation in a single gene, these conditions seem to arise from a combination of genetic, behavioral, and environmental factors. Researchers believe that a host of genetic variations may contribute to a person’s susceptibility. For instance, David Hafler, at Harvard Medical School and Brigham and Women’s Hospital, points out that in multiple sclerosis, “ each gene contributes only a small amount of risk. The big question is, how do they interact with each other, and are they in common pathways ”

Genomic technologies have now made it possible to uncover these subtle genetic associations. “ People have been looking for genes involved in multiple sclerosis for 30 years,” Hafler says. “ Why weren’t they found" The answer is you couldn’t do it without the sequence of the human genome.” Collaboration with Eric Lander at the Broad Institute of Harvard and MIT, a leader in the effort to sequence the human genome, was critical. The next step, Hafler said, is to begin to collect larger numbers of samples and examine more DNA sequences, which will allow researchers to identify subtler variations that contribute to the disease.

Source: Harvard Medical School, 2007

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