Behcet’s Disease Has Genetic Link To Ancient Silk Road Trade Route
January 7, 2013

Behcet’s Disease Has Genetic Link To Ancient Silk Road Trade Route

Lawrence LeBlond for - Your Universe Online

Researchers continuing the study of the human genome have mapped out four new regions that are associated with a painful and often dangerous condition–Behcet´s disease–found in people with a lineage to ancestors along the Silk Road.

The Silk Road was used as an important trade route for nearly 2,000 years, linking the Far East and Europe. But along with the trade of goods and cultures, also came the exchange of disease and gene pools.

Now, researchers with the National Institutes of Health (NIH), in collaboration with Turkish and Japanese colleagues have published findings of the genetic link between Behcet´s disease and the Silk Road in the January 6 online issue of Nature Genetics.

Named for the Turkish physician who first described the condition in 1937, the disease is triggered by complex genetic and environmental factors. Common symptoms of Behcet´s include painful mouth and genital sores, and eye inflammation that can lead to blindness. In can be life-threatening if left untreated, as it also affects blood vessels in the brain, lungs and other vital organs.

About 1 in 250 people in Turkey have Behcet´s disease, and others with the disease are largely found in regions associated with the Silk Road.

Researchers have surmised that genetic factors play a key role in susceptibility of the disease, with the human leukocyte antigen (HLA) B-51 gene region of the genome accounting for 20 percent of the genetic risk for the disease. Researchers have been aware of this association for at least 40 years. And two years ago, the team was able to identify gene associations with two other specific chromosome locations (loci).

Senior study author Dan Kastner, MD, PhD, scientific director of the Intramural Research Program at the National Human Genome Research Institute (NHGRI), said: “The current study represents an important advance because it dramatically broadens the spectrum of genetic loci associated with Behcet's disease.”

“These newly discovered genetic associations provide a link between Behcet's disease and other more common illnesses, and thereby suggest new therapies for Behcet's disease. In addition, two of the newly discovered genes provide an intriguing link between genes and the microbes in our environment.”

The new gene locations were found while conducting a genome-wide association study (GWAS) that enrolled more than 1,200 Turkish people affected with Behcet´s and nearly 1,300 not affected by the disease. The researchers studied many points on the human genome called single-nucleotide polymorphisms (SNPs), with each SNP representing a difference in a single DNA building block (nucleotide). The team then compared SNP differences between both sets of people.

From nearly 800,000 SNPs, the team detected and mapped a small number that are found in those who have Behcet´s at a significantly higher rate than those without the disease, suggesting that a variant contributes to the disease.

"Each of the genetic factors may contribute a little to the overall risk of disease," study coauthor Elaine F. Remmers, PhD, staff scientist in NHGRI's Inflammatory Disease Section, said in a statement. "We are also identifying them in pathways that are important in inflammatory disease development."

Rather than genotyping all 800,000 gene variations observed, Remmers said the team used a different strategy–imputing that there were genotypes worth investigating near known variants.

"That worked very well for us," Remmers said. "We found that our predicted genotypes were pretty good and that the associations we found were quite similar in both the predicted and the experimentally confirmed genotypes."

Each of the four newly identified gene regions is already known to play a role in immune regulation. And the genetic associations have helped researchers classify Behcet´s with more common inflammatory conditions such as psoriasis, ankylosing spondylitis and inflammatory bowel disease.

In the four newly identified regions, the researchers found associations between Behcet´s and the genetic variants of ERAP1, CCR1, KLR4, and STAT4.

The association with ERAP1 and its variants identified in this study increase the risk of Behcet´s disease, but only in individuals with the HLA-B51. Dr. Kastner speculates that the ERAP1 variant associated with Behcet's disease processes microbial proteins in such a way that they can be loaded onto the HLA-B51 molecule to trigger an abnormal immune response.

The CCR1 gene and its variants are coded in proteins that help infection-fighting blood cells migrate to sites of invading microorganisms. When this function is defective, the microorganisms can trigger a persistent inflammatory response.

The function of the receptor protein coded by the KLRC4 gene and its variants are not well understood, but the researchers suggest that it may be important to investigate further because it is located within the genomic region with the strongest evidence for linkage to a disease gene in a study of Turkish family health histories in which members sometimes have a rare familial form of Behcet's disease.

The STAT4 gene and its variants increase the risk for autoimmune diseases, such as rheumatoid arthritis and lupus.

"We are incredibly excited about these latest findings," Kastner said. "Combined with our studies two years ago, the current genetic data make a strong case for a causal connection between Behcet's disease and disorders such as ankylosing spondylitis, psoriasis, and inflammatory bowel disease.”

“This raises real hope that some of the treatments that have been found effective in these other illnesses will have some utility in Behcet's disease, thereby helping to alleviate suffering and prevent mortality,” concluded Kastner.