Honing in on the Genetics of MS

WEDNESDAY Aug. 10, 2011 -- A new study on the genetic underpinnings of multiple sclerosis (MS) has identified more than 50 gene variants that may contribute to the autoimmune disease, 29 of which are new discoveries.

About half of the variants are known to be involved in immune system function, and about one-third have been implicated in other autoimmune diseases, such as Crohn's, celiac disease, rheumatoid arthritis, lupus and type 1 diabetes.

"When we look at the pathways, they are telling us loud and clear the earliest stages of this disease process involves some dysregulation of the immune system, particularly involving T lymphocytes," said co-principal investigator Dr. Alastair Compston, a professor of neurology at University of Cambridge in England.

T lymphocytes are immune cells that carry out surveillance against infections. In autoimmune diseases, it's believed that the lymphocytes mistake body tissues as foreign and attack those.

In the case of MS, the body's own immune system attacks myelin, or the substance that insulates nerve fibers of the central nervous system. The damage disrupts nerve signals traveling to and from the brain, which can lead to numbness, movement difficulties, blurred vision, fatigue and eventually, cognitive problems.

The study included nearly 10,000 MS patients from 15 countries and more than 17,000 healthy controls. The research, a genome-wide analysis, was conduced by the International Multiple Sclerosis Genetics Consortium, a group made up of researchers from 129 institutions studying the genetics of MS.

The large sample size enabled researchers to identify more variants, called single nucleotide polymorphisms, than had been found in prior research, researchers said.

Knowing which genes play a role in MS may help pave the way to new treatments, including the possibility that the commonalities between MS and other autoimmune diseases could mean that certain treatments already in use might work on more than one of the diseases.

"The general processes that go on in autoimmunity are shared," Compston said. "But why that common set of problems leads to diabetes in one and MS in another remains to be solved."

The study was published in the Aug. 11 issue of Nature.

The first discoveries about a genetic basis for MS were made in the 1970s, when researchers found an association with the HLA (human leukocyte antigen) region, a group of genes on Chromosome 6.

Yet after that, for many years "there has really been a resounding silence on the specifics of the genetic basis for MS, despite an enormous amount of effort," Compston said.

That started to change a few years ago as the ability to analyze genes improved, explained Margaret Pericak-Vance, director of the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine.

"MS is a complex disease. We know that. For a long time, we've known that genetics has played a role. But when we first started looking at the genetics, we thought it was going to be a simple answer," Pericak-Vance said. "They identified HLA over 30 years ago as being involved in MS. Yet over time, we found out, it's not that easy. MS is very heterogeneous. HLA doesn't account for all of it, so we waited for technology to become available to learn more."

Over the past two years, numerous studies have uncovered other genes that are involved, she added. In adding so many new variants to that list, the current study "helps us understand more about the genetic landscape underlying MS," she said.

MS is currently treated with immunological drugs, but they're not perfect, Compston said. "This study absolutely gives the authority to press on with that particular strategy and to solve the problems around the safety and efficacy of these drugs," she noted.

And given that so many of the new genes identified are involved with immune system function, it should put to rest any lingering doubts that MS is indeed an autoimmune disease, Compston said.

Although genes matter, so do environmental factors in triggering MS, experts said. And even the expanded list of more than 50 genetic variations doesn't explain all cases of MS.

"Even though MS is different from lupus and other autoimmune diseases, because of the common genes, there are some basic mechanisms that are the same across these disorders," Pericak-Vance said. "Understanding those basic mechanisms, plus what is different, may help in coming up with new therapies and new targets."

While the paper explains a certain percentage of MS, it doesn't explain all, she added. "There are still genetic contributions we don't know yet," she said.

More information

The National Multiple Sclerosis Society has more on MS.

Posted: August 2011


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