New clues: gene variations may contribute to MS risk.

Certain versions of two genes show up in multiple sclerosis patients more often than in people without the disease, researchers report. Although these variations modify the usual roles of the genes only in subtle ways, scientists suspect that they are part of a network of dozens of gene variants that contribute to the disease.

Multiple sclerosis (MS) clearly has a hereditary component. A person whose identical twin has MS has a nearly one-in-three chance of developing it, compared with the average risk of about 1 in 1,000.

In the 1970s, scientists found that a specific version of a gene encoding human leukocyte antigen DRB1, an immune system protein, conferred a fourfold increase in the risk of MS. But the variant fell far short of accounting for all genetic risk associated with the disease. Two studies in the United States and one in Sweden now fill in more of the picture, indicating that people with MS are 20 to 30 percent more likely than those without the disease to have a particular form of another immunity-linked gene. The gene encodes the receptor for the immune messenger protein interleukin-7.

The researchers used whole-genome scanning and other new techniques to analyze DNA from more than 20,000 people in the United States and Scandinavia, some with MS and some without. Two of the studies will appear in an upcoming issue of Nature Genetics and the third in the New England Journal of Medicine. The latter report also links to MS a variant form of another gene, which encodes interleukin-2 receptor alpha.

The interleukin-7 receptor is typically attached to the membrane of cells, most often immune system T cells. When interleukin-7 binds to it, the receptor signals the cell to take part in immune reactions.

The variant of the interleukin-7 receptor gene seems to slightly favor production of a free-floating, or soluble, version of the receptor. Soluble receptors compete with the membrane-bound receptors for interleukin-7, says immunologist Jorge R. Oksenberg of the University of California, San Francisco, who coauthored two of the studies. An excess of soluble receptors might therefore "affect the fine-tuning of immune responses," he says.

The interleukin-7--receptor variant identified in this study is far from rare, showing up in roughly 70 percent of people of European descent. Nonetheless, "it's overrepresented in MS patients," says Ursula Utz, a molecular biologist at the National Institute of Neurological Disorders and Stroke in Bethesda, Md. She predicts that as many as 30 genes might ultimately be found to contribute to MS. The remainder of MS risk apparently stems from environmental factors, perhaps including childhood exposure to sunlight (SN: 7/28/07, p. 51).

In MS, an inflammatory reaction depletes the fatty sheaths that protect nerve fibers, causing a loss of muscle control. Even so, debate has lingered over whether MS is truly an autoimmune disease.

"I think this cinches it," says Margaret A. Pericak-Vance, a geneticist at the University of Miami who also worked on these studies. Adding to the evidence is the fact that interleukin-2 receptor-alpha has recently been linked to Graves' disease and type 1, or juvenile-onset, diabetes. Like MS, these diseases have autoimmune traits.