Genome-wide association studies (GWAS) are examining the human genome in ever-greater depth in the hope of finding common variants that explain the heritability associated with common diseases such as coronary artery disease. Despite the ever increasing scale of these big-science ‘super-projects’ with literally tens of thousands of cases and controls, only a small proportion of heritability has thus far been explained. GWAS by their very nature only identify regions of the genome associated with disease risk, and say nothing as such about the actual mechanism through which this risk is conferred.
One locus, however, that has been repeatedly implicated is the 9p21 region. Since the identification of 9p21, work has been underway to characterize the elements within this region and ascertain their function. Interestingly, this region is a gene-desert with a dearth of classical coding gene elements, but in this study the authors identify 33 regulatory elements called enhancers and furthermore identify that one of these enhancer elements (ECAD 9) specifically contains two polymorphisms which have been identified as increasing risk. The polymorphisms disrupt a binding site for the transcription factor STAT 1 which regulates gene transcription in response to interferon signaling. In a cellular model the authors go on to show that interferon-λ strongly influences the activation of this region through STAT 1, and that the aberrant binding induced by the polymorphisms can influence gene regulation in distant regions of the genome mediating responses to inflammation, which may therefore drive angiogenesis and the pathogenesis of atherosclerosis.
In this elegant study of cellular biology the authors demonstrate the underlying mechanism governing the risk associated with polymorphisms of the 9p21 region. Further work may elucidate novel pathways and targets in the prevention and treatment of coronary artery disease.
- Harismendy O, Notani D, Song X, Rahim NG, Tanasa B, Heintzman N, Ren B, Fu XD, Topol EJ, Rosenfeld MG and Frazer KA. 9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response. Nature. 2011 Feb 10;470(7333):264-8.