A pair of large-scale genetic studies supported by the National Institutes of Health has revealed two genes that influence the risk of getting multiple sclerosis (MS) -- data sought since the discovery of the only other known MS susceptibility gene decades ago. The findings could shed new light on what causes MS -- a puzzling mix of genes, environment and immunity -- and on potential treatments for at least 350,000 Americans who have the disease.
"These studies describe the first genes conclusively linked to MS in more than 20 years," said Ursula Utz, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke (NINDS), a part of NIH. "This breakthrough was made possible through persistence, an elegant search strategy, and genomic data and techniques that were not available until recently."
Both studies involved scanning DNA samples from more than 20,000 MS patients and unaffected individuals in the U.S. and Europe, and looking for single nucleotide polymorphisms (SNPs), which are single-letter variations in a gene's DNA code. Published simultaneously in the New England Journal of Medicine and Nature Genetics, the studies demonstrate an association between MS and SNPs in two genes that encode interleukin receptors, proteins that serve as antennae on the surface of immune cells.
Both studies were supported by NINDS and the National Multiple Sclerosis Society. The Nature Genetics study received additional support from the National Institute of General Medical Sciences (NIGMS). The NEJM study was also supported in part by the Penates Foundation.
They were conducted by overlapping teams of scientists that used different gene-hunting strategies. One team, which scanned the entire human genome for MS risk factors, was co-led by David Hafler, M.D., Professor of Neurology at Harvard Medical School and Brigham and Women's Hospital in Boston, Stephen Hauser, M.D., Professor and Chair of Neurology at the University of California in San Francisco, and Alastair Compston, FRCP, Ph.D., Head of the Department of Clinical Neurosciences at the University of Cambridge, U.K. The other team, which focused their search on a set of genes they considered potential risk factors for MS, was co-led by Jonathan Haines, Ph.D., Director of the Center for Human Genetics Research at Vanderbilt University Medical Center in Nashville, Tenn. and Margaret A. Pericak-Vance, Ph.D., Director of the Miami Institute for Human Genomics at the University of Miami. Drs. Hauser, Compston, Haines and Pericak-Vance participated in both studies.
MS typically causes limb weakness, vision loss and problems with coordination, and is the most common disabling neurological disorder of young adults. It's an autoimmune disease, occurring when the body's immune system mistakenly attacks a protective sheath around axons -- the delicate cables that nerve cells use to connect with each other. Various immunosuppressant drugs can reduce symptoms and slow the disease's course, but most MS patients become increasingly disabled with time.
The trigger for MS is unclear, though there's strong evidence for an interplay between genetic susceptibility and some type of environmental factor. Having a relative, especially an identical twin, with MS increases one's risk of developing the disease. In the mid-1970s, researchers discovered that human leukocyte antigens (HLA) account for some of this genetic susceptibility. HLAs are proteins displayed on all the body's cells to help the immune system distinguish self from non-self. A variant of the HLA-DRB1 gene, now widely accepted as the strongest genetic risk factor for MS, increases the likelihood of getting the disease up to four-fold.
Still, HLA does not fully explain the genetic basis of MS; scientists have long realized that other genes must play a role that has been difficult to detect. Some studies have pointed to other HLA genes, but neither of the two genes reported today belong to that category. Both genes encode receptors on the surface of T cells -- the immune system's mobile infantry -- that enable the cells to respond to regulatory, secreted proteins called interleukins.
"These are the first non-HLA genes to be unequivocally associated with MS," said Dr. Pericak-Vance. "They give us a new way of looking at the biology of the disease, and could be targets for therapeutic development."
Both studies searched for a link between MS and SNPs that were previously identified by the HapMap, an NIH-supported project to catalog genetic differences in human populations.
In the genome-wide association study, the first of its kind in MS, the researchers used gene chip technology to scan more than 500,000 SNPs. In total, they analyzed more than 13,000 DNA samples, many of them collected and stored by the Center for Genetic Studies at the National Institute of Mental Health (NIMH) and the U.K.'s Wellcome Trust Case Control Consortium. In the candidate gene study, the researchers scanned DNA samples from four large groups in the U.S, U.K. and Belgium, totaling more than 10,000 people.
Both studies revealed an association between MS and a single SNP in the gene interleukin 7 receptor-alpha (IL7R-alpha). The genome-wide scan also found two SNPs in the gene for interleukin 2 receptor-alpha (IL2R-alpha) associated with the disease. Both receptors are known to influence the way that T cells patrol the body for pathogens. IL2R-alpha has previously been implicated in other autoimmune diseases, including type 1 diabetes.
Each of the SNPs associated with MS appears to increase the risk of developing the disease by about 20 to 30 percent. Although that number might seem small, "it's the size of effect we expect to see for genes outside of HLA," said Dr. Haines. Multiple genetic variations, each carrying a small risk of MS, could combine with one another and with environmental factors to create a large risk, he said.
The researchers who conducted the candidate gene search also think they know how variation in the IL7R-alpha gene affects the IL7R-alpha protein. They found evidence that the MS-associated variant causes a reduction in the amount of the IL7R-alpha protein at the T cell surface. Less is known about how variation in IL2R-alpha might contribute to MS, but that protein is already being viewed as useful therapeutic target. In a 2004 study by NINDS scientists, 10 MS patients who were unresponsive to currently approved therapies showed improvement when treated with an antibody that blocks IL2R-alpha, developed to prevent rejection of organ transplants.
Finally, the genome-wide scan identified nearly a dozen other genes that could represent risk factors for MS. Some of the associations were relatively weak and some of the genes' functions are unclear.
"A major effort to understand the full complement of genes involved in MS will be necessary to completely understand the disease," said Dr. Hafler, adding that all of the data from the genome scan will be made publicly available for future investigations.
The International Multiple Sclerosis Genetics Consortium. "Novel Risk Alleles for Multiple Sclerosis Identified by a Whole Genome Association Study." New England Journal of Medicine, published online July 29, 2007.
Gregory SG et al. "Allelic and Functional Association of the Interleukin 7 Receptor alpha Chain (IL7R-alpha) with Multiple Sclerosis." Nature Genetics, published online July 29, 2007.
Materials provided by NIH/National Institute of Neurological Disorders and Stroke. Note: Content may be edited for style and length.
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