U.S. researchers have shed new light on the previously flagged link between SNPs at chromosome 9p21 and coronary artery disease (CAD), type 2 diabetes, and other vascular diseases. The scientists, including teams at Scripps Translational Science Institute (STSI) and Scripps Health, suggest the functional link may relate to CAD-associated SNPs in an enhancer element that affects binding of the regulatory protein STAT1, which is involved in the inflammatory response. They also found the region to be influenced by interferon-gamma, which itself can affect how local chromatin is organized in three dimensions, so affecting STAT1-binding and the expression of nearby genes.
Their studies will be published tomorrow in Nature, in a paper titled "9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response".
The researchers used a multipronged approach involving cellular assays and population sequencing to identify and functionally characterize variants underlying the 9p21 association with CAD. This included analyzing the genetic profiles of 50 adults of European ancestry enrolled in the STSI biobank repository. Their studies identified 33 enhancers in the 9p21 region, which they describe as the second densest gene desert for predicted enhancers, and six times denser than the whole genome.
“We had been perplexed as to how the specific location of genome has influenced not just heart attacks but abdominal aortic aneurysms and intracerebral artery aneurysms—so not just atherosclerosis by any means,” notes Eric J. Topol, Ph.D., chief academic officer at Scripps Health and corresponding co-senior author of the Nature paper. “Now we know it has to do with inflammation of the artery wall. This was quite an extraordinary hunt to find how the risk DNA variant was exerting its effect, and it turned out to be quite remote through a gene known as STAT-1, a vital mediator of inflammation.”