July 19, 2010

Unraveling a Silk Road Disease Mystery

Photo of people riding camels past sand dunes Tourists ride camels along the Silk Road in Dunhuang, China.Linda Wang.

Researchers have identified several genetic regions associated with Behçet's disease, a painful and potentially dangerous condition found almost exclusively in people with origins along the Silk Road, a trading route that stretched from Europe to the Far East.

Although the Greek physician Hippocrates described Behçet's disease (pronounced BET'-chet's) more than 2,000 years ago, it is named for the Turkish physician who first classified it in 1937. Behçet's disease is marked by painful ulcers affecting the mouth and genitals, and by inflammation of the skin and eyes. Recurrent inflammation in the eyes, brain and large blood vessels can cause severe complications. Treatments for Behçet's disease currently target symptoms rather than addressing an underlying mechanism.

The distinctive distribution of Behçet's disease led researchers to suspect a hereditary component. However, even the most strongly associated genetic factor to date—HLA-B51—accounts for less than 20% of the genetic risk for the disease. To look for other factors, researchers led by Dr. Elaine F. Remmers of NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), in collaboration with Dr. Ahmet Gul's group at Istanbul University, performed a large genome-wide association study (GWAS) of people from Turkey. The researchers examined the genomes of more than 1,200 Behçet's patients and 1,200 people without the disease, looking for tiny differences, called single nucleotide polymorphisms (SNPs), between the groups.

In the advance online edition of Nature Genetics on July 11, 2010, the scientists confirmed the association of HLA-B51 with the disease. The team also identified HLA-A as another region associated with Behçet's disease. Both HLA-A and HLA-B51 are found in a section of the genome known as the major histocompatibility complex (MHC). The MHC contains a large number of immune-related genes.

The researchers also found other potential links. To better evaluate these, they exchanged data with another group of investigators that independently performed a large GWAS for Behçet's disease in a Japanese population. That group's paper appeared in the same edition of Nature Genetics. The NIAMS researchers analyzed genetic data from 5 additional groups as well, which included populations from Turkey, the Middle East, Europe and Asia.

The researchers found associations with Behçet's disease in a known variant of the IL10 gene and in a variant located between the IL23R and IL12RB2 genes. Interestingly, the variants associated with disease in the Turkish population were identical to those in the Japanese population. This finding lends credence to a genetic link between 2 disparate populations separated by thousands of miles but tied together by the ancient trading route.

IL-10 protein is known to decrease inflammation. IL10 variants have been tied to other autoimmune and autoinflammatory diseases, including ulcerative colitis, type 1 diabetes and juvenile rheumatoid arthritis. The researchers found that people who had 2 copies of the IL10 variant produced significantly lower levels of IL-10 protein than those with normal versions of the gene.

"We knew that Behçet's disease had a strong genetic component, but until now, we haven't been able to search the entire genome to identify hidden candidate genes," Remmers says. These findings suggest potential therapeutic targets for future study.

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