Editors' ChoiceCardiovascular Genomics

Coronary Artery Disease Decoded

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Science Translational Medicine  02 Mar 2011:
Vol. 3, Issue 72, pp. 72ec26
DOI: 10.1126/scitranslmed.3002292

In the last five years, genome-wide association studies (GWASs) have identified nearly 1000 single-nucleotide polymorphisms (SNPs) that are strongly tied to the susceptibility to over 100 diseases and traits. One of the most remarkable of these discoveries has been the link between common chromosome 9p21.3 variants (present in about 25% of Europeans) and a doubling in the risk for heart attack. Curiously, these 9p21 susceptibility SNPs reside in a genomic desert, with the closest genes being more than 125,000 base pairs away.

Now, Harismendy et al. demonstrate that the 9p21.3 locus is most likely exerting its effects through key inflammatory pathways triggered by local and long-distance gene interactions. In order to determine this, they first examined transcription factor binding and chromatin modification profiles in various human cell lines, which revealed that the 9p21.3 region contains over 30 enhancers—one of the highest densities for predicted enhancers in the human genome. Second, through computational modeling they found that the 9p21.3 SNP rs10757278, which is the SNP most consistently associated with coronary artery disease in previous GWASs, resides within an enhancer site (ECAD9) and disrupts the binding of STAT1—a transcription factor critically involved in inflammation and interferon-γ (INF-γ) signaling.

Subsequently, the investigators showed that signal transducer and activator of transcription 1 (STAT1) binding to the ECAD9 site in human umbilical vein endothelial cells increased in the presence of INF-γ, but not in cell lines homozygous for the coronary artery disease–associated SNP rs10757278. Moreover, INF-γ and STAT1 binding inversely correlated with the expression of CDKN2B, which codes for a cell cycle regulator and is the closest gene to the 9p21.3 interval. Lastly, using a method known as chromatin conformation capture (3C), the investigators observed that INF-γ triggered genomic interactions between 9p21.3 enhancers and the gene IFNA21 (interferon-α 21)—located 946,000 bases downstream on chromosome 9—as well as with other nearby and distant genes.

For years, epidemiologic data has suggested that inflammation is central to the progression and development of atherosclerotic coronary artery disease. Now, this study indelibly links inflammation to not only coronary artery disease but to other 9p21.3-associated phenotypes, including intracranial and abdominal aortic aneurysm. Going forward, much work remains to be done because 9p21 variants explain only a small percentage of the heritability for coronary artery disease and are a significant risk factor only for those of European ancestry.

O. Harismendy et al., 9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response. Nature 470, 264–268 (2011). [Abstract]

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