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New genes discovered for multiple sclerosis

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  • New genes discovered for multiple sclerosis

    July 29, 2007 -- The best way to understand a disease is to get at its root cause, and most of the time, that means hunting down the genes that trigger it. In three papers published this week, researchers report that they have identified two new genes that may contribute to the immune disorder multiple sclerosis (MS). The hope is that the discovery will someday lead to the development of more efficient and much-needed MS drugs, as today's therapies carry serious side effects and address the disease's symptoms, but not its cause.

    The new genes are the first to be linked directly to MS since the 1970s, when researchers initially identified a cluster of DNA on chromosome 6 associated with immune system function. Doctors believe MS is an autoimmune disease, in which the body mistakenly attacks its own healthy cells. But they have never been able to figure out why the body turns on itself, and they hope these new genes may offer a clue. "This is by no means the final, whole answer, but we've gotten an incredible glimpse into the cause of the disease," says Dr. David Hafler, professor of neurology at Harvard Medical School and Brigham and Women's Hospital and an author of one of the papers, which appears in the New England Journal of Medicine. In the other reports, published in Nature Genetics, two independent research teams confirmed the role of one of the genes described by Hafler's group.

    For decades, MS researchers have been forced to make their best guess as to what causes the disease, which affects 300,000 Americans, mostly women, between their 20s and 40s. Since 1990, thanks to work done in Hafler's lab, however, they've known that MS sufferers have hyperactive T cells — cells that cruise the body looking for bacteria, viruses and other pathogens — a condition that triggers an inflammatory response and destroys the protective myelin sheath around nerve cells in the central nervous system, which connects the brain and body. This can lead to gradual nerve damage and weakening of the muscles in the arms as legs, as well as problems with vision.

    What doctors didn't know was why these immune cells went into a hyperalert state to begin with. Was it caused by a virus? Was it nutritional, as suggested by a study last week in the journal Neurology, which found that having too little vitamin D, normally produced in the body during exposure to sunlight, increases the risk of MS? Or, were genes to blame for inciting the immune system to rebel? Or, was it, as most experts believe, some combination of all of the above?

    To get a better answer, leading MS scientists in the U.S., including Hafler, teamed up with researchers in England and formed the International Multiple Sclerosis Genetics Consortium in 2002. The plan was to take their genetic study to the next level. So, they pooled their resources and examined the entire genomes of more than 2,000 MS sufferers, their families and control subjects. "People had been studying the genetics of MS for 20 years, and nothing had come out of it," says Hafler. "I felt we needed a genetic roadmap to show us what pathways to study that would help to explain the disease."

    What they found were two new genes, IL2 and IL7, which code for receptors for interleukin — the proteins that regulate how T cells work in the body. People with certain forms of these genes have a 20% increased risk of developing MS. It is not, however, a defective or mutated form of the genes that causes MS; rather, it's certain forms of the genes, known as variants, that increase risk. The etiology of MS is complicated and appears to involve many genes, so the next challenge will be to figure out precisely what role these two new genetic variants play.

    As exciting as the discovery is, it's a small part of the story: the new genes account for less than 1% of the risk of developing MS. In addition, about 70% of the normal, non-MS affected population has the same variants. "Every single time we have looked for genes for MS, the genes turn out to have a very small effect," says Dr. Moses Rodriguez, professor of immunology at the Mayo Clinic and a leading MS researcher." That suggests that either the disease is not genetically controlled in a significant way, or that if it is, that there are at least a 100 or so more genes that account for the entire disease process."

    Hafler acknowledges that these findings are only the first step. Uncovering additional genes will require analyzing an even larger pool of MS patients and their families — Hafler is hoping to find at least 9,000 more patients. He calculates that with that much DNA, he'll be able to tease out 90% of the genetic culprits involved in MS. "These first genes give us a working hypothesis for what may be causing MS," says Hafler, "and a lot more work needs to be done. But we have finally begun."

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