A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression

作者：Gupta Rajat M; Hadaya Joseph; Trehan Aditi; Zekavat Seyedeh M; Roselli Carolina; Klarin Derek; Emdin Connor A; Hilvering Catharina R E; Bianchi Valerio; Mueller Christian; Khera Amit V; Ryan Russell J H; Engreitz Jesse M; Issner Robbyn; Shoresh Noam; Epstein Charles B; De laat Wouter; Brown Jonathan D; Schnabel Renate B; Bernstein Bradley E; Kathiresan Sekar

来源：Cell, 2017, 170(3): 522-+.

DOI：10.1016/j.cell.2017.06.049

Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases.

• 出版日期2017-7-27