Hard on the Nerves

The genes that make some people susceptible to multiple sclerosis (MS) have eluded scientists for more than 30 years. Now, three studies by researchers in Europe and the United States implicate a pair of immune system genes in the nerve-eroding illness. The findings could eventually lead to new ways of diagnosing and treating the disease.

MS causes symptoms such as muscle weakness and difficulty speaking. Researchers believe it's likely an autoimmune disease, in which lymphocytes and other immune system cells attack the brain, optic nerve, and spinal cord. Genes and unknown environmental factors conspire to set off the nerve destruction. About 30 years ago, scientists found a link between MS and certain variants in the major histocompatibility complex (MHC), a cluster of genes that help the immune system distinguish between the body's own proteins and those of microbial invaders. However, because the MHC variants account for less than half the genetic risk of contracting the disease, other genes had to be involved. Their discovery had to wait for the sequencing of the human genome and other advances in gene-finding techniques.

To nail down these evasive genes, teams led by human geneticist Jonathan Haines of Vanderbilt University in Nashville, Tennessee, and neurologist Jan Hillert of the Karolinska Institute in Stockholm, Sweden, compared several thousand MS patients from the United States and Europe with their family members and healthy controls. The teams used different genetic approaches, but both found that one variant of a gene called IL7R boosted MS risk by about 30%. This gene codes for part of a protein complex, called the IL-7 receptor, that is found on the surface of certain lymphocytes and is important for their maturation. The researchers describe their findings in the 29 July issue of Nature Genetics.

Using a third approach, neurologist David Hafler of Harvard Medical School in Boston and colleagues also identified the IL7R variant as a risk factor in 1540 MS patients and their parents. In addition, they identified two variants in a second immune system gene, IL2RA, which codes for a protein called the IL-2 receptor. As the team reports in the 29 July New England Journal of Medicine, these variants increased the odds of developing the illness by about 20%. The IL-2 receptor has already been linked to other autoimmune diseases such as type 1 diabetes and Graves' disease.

George Ebers, an MS researcher at Oxford University in the U.K., says that the new findings are "important conceptually" but may not easily translate into therapeutic advances. For example, Ebers says, the new research also shows that the IL7R variant associated with increased MS risk is present in 70% of people of European descent, suggesting that many other genetic factors are involved because few of these people contract MS. "The most striking finding," Ebers says, "is the degree of genetic influence [on MS] that remains unexplained."

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