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First new multiple sclerosis gene found in 30 years

July 30, 2007

DURHAM, N.C. -- A newly identified gene may hold the promise of guiding future research into therapies for multiple sclerosis in what its discoverers say is the first major genetic advance in 30 years for understanding this nervous system disease.

While it has been known that there is a strong genetic underpinning for multiple sclerosis, only genes within a region of chromosome 6 have to date been implicated in the disease. The current finding, reported early online July 29 in the journal Nature Genetics, demonstrated that a functional gene variant on chromosome 5 was associated with an increased susceptibility to the disease. The study was supported by the National Institutes of Health

"Our finding is very important because the genetic factors that are already known to be associated with multiple sclerosis only explain less than half of the total genetic basis for the disease," said Simon Gregory, Ph.D., molecular geneticist at Duke's Center for Human Genetics and first author of the paper. "We have identified a gene that increases an individual's risk of MS by 30 percent and that this variant has an effect on the function of the gene."

It is likely that variants of many genes are associated with the development of multiple sclerosis, so identifying a novel gene that is associated with MS will be very helpful in understanding this complex disease."

Joining Gregory and his colleagues at Duke were researchers from the University of California at San Francisco and the University of Cambridge in the United Kingdom, who spearheaded the collection of multiple sclerosis populations over many years, and the University of Miami and Vanderbilt University. The same team was also involved in another paper replicating similar findings from a whole genome analysis, which will appear on line in the New England Journal Medicine on July 29th.

Multiple sclerosis is a disease that is caused by the breakdown of the fatty sheath surrounding axons, the long spindly portions of nerve cells that carry messages from one cell to another. This sheath, known as myelin, acts much like the plastic coating insulating an electrical cord.

For reasons that are not well understood, the body's own immune system is believed to attack the myelin, which can cause "short circuits" in the body's electrical system. This leads to the symptoms of the disease, which include muscle weakness, cognitive impairment, difficulties with balance and coordination, and speech and vision problems. What triggers this autoimmune response is likely a result of a complex interplay between genetic and environmental factors, Gregory said.

The previously discovered multiple sclerosis genes were all located in an area of chromosome 6 involved in the major histocompatibility complex, which is important in the regulation of the immune system. The gene variation discovered in the most recent research is located on chromosome 5, and is involved in guiding the production of interleukin-7 receptor alpha (IL-7R), which is a critical receptor for the development and growth of key immune system cells.

Gregory said that as research builds upon the altered function of IL-7R the mechanisms involved in the development of multiple sclerosis will be unlocked, which may lead to novel treatments for the disease or the identification of targets for new therapies.

The team used a technique known as genomic convergence, in which they took the results of many studies looking for common elements. From studies involving patients and their families in the United States and Great Britain, they analyzed more than 7,000 DNA samples from patients with confirmed multiple sclerosis and those without the disease After winnowing down 28 candidate genes to the IL-7R gene, the researchers then tested their findings on a different set of patient populations to confirm their findings.

"One of the greatest challenges in any effort to identify genes for complex diseases like multiple sclerosis is to see if results from one study population can be confirmed in others" said Silke Schmidt, Ph.D., co-first author of the paper who is also at the Duke Center for Human Genetics. "We showed that the exact same genetic change in IL-7R increased the risk of multiple sclerosis to a very similar extent in four different populations."

Multiple sclerosis is most common in young adults, with more than 90 percent of the cases being diagnosed before the age of 55, and fewer than five percent diagnosed before the age of five. Women are two to three times more likely to develop the disease, which afflicts about 350,000 patients in the United States.

Duke University Medical Center