Scientists pinpoint 2 DNA variants linked to MS

BY DELTHIA RICKS

delthia.ricks@newsday.com

July 29, 2007, 6:12 PM EDT

In what is being hailed as a genetic bonanza, scientists have pinpointed two key DNA variants that elevate the risk of multiple sclerosis.

Since 1868 when the degenerative neurological disorder was first described, medical investigators have tried to shed light on its underlying cause. And even now with the announcement of two genetic discoveries -- the first in more than three decades -- scientists say they still have years to go before they fully understand MS.
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"We have been working on this for 25 years so this is a landmark achievement for MS, but we have a long way to go," said Dr. David Hafler, the Breakstone professor of neurology at Harvard Medical School and Brigham and Women's Hospital in Boston.

An estimated 400,000 people in the United States have MS, the most common neurological disorder in people 40 and younger.

Five years ago, Hafler organized the International Multiple Sclerosis Genetics Consortium, pooling the talents of the world's top experts to accelerate the gene hunt. The consortium scanned the entire human genome, using DNA samples from more than 12,000 people.

What they found, Hafler said, was a stunning genetic relationship between multiple sclerosis, type 1 diabetes and the thyroid condition known as Graves' disease. Type 1 diabetes and Graves are two major autoimmune diseases characterized by the body's capacity to attack itself, a key characteristic of MS.

One of the newly identified MS genes is known as the IL-2 receptor, which previously had been linked to type 1 diabetes and Graves. The other is called IL-7. When healthy, both are intimately involved in the body's immune response.

Prior to today's announcements, the only other DNA links to MS were discovered in the 1970s when British scientists spotted a large DNA cluster known as MHC -- the major histocompatibility complex -- which is flawed in patients with the condition. This segment of DNA also is responsible for many immune functions, Hafler said.

Given the complexity of MS, Hafler added, scientists were certain that a constellation of genes that included MHC must be related to the disorder. That notion, he said, inspired the hunt for additional suspects.

"We did a scan of the whole genome," Hafler said, describing a sweeping search of the entire complement of human genes to find those related to MS. "We didn't focus on one spot, looking for a single lamp post. We searched everywhere."

Even though multiple sclerosis is a neurological condition, scientists also believe that it is an autoimmune disease, driven by turncoat components of the immune system, explained Simon Gregory, a molecular geneticist at Duke University. Gregory pinpointed IL-7's exact location on chromosome 5. People have 46 chromosomes, 23 inherited from each parent.

In MS, turncoat immune-system cells attack the insulating fatty coatings of nerves -- the myelin sheath. With the sheathing destroyed, nerve function is damaged, causing a range of symptoms from muscular weakness and loss of coordination to speech and visual disturbances. The disorder primarily occurs during young adulthood.

Gregory added that MS also must have an environmental trigger, perhaps a viral infection that sets off the cascade of ill-fated genetic events.

In Manhattan, Dr. John Richert, executive vice president of research for the National Multiple Sclerosis Society, said there is practical meaning in the discoveries. Scientists now have new targets for diagnostics and therapeutics.

"These advances open a door for a landslide of new gene discoveries for MS," Richert said.

The complete report of the consortium's research is posted in the online edition of the New England Journal of Medicine. Gregory's analysis is published in Nature Genetics.

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