| Literature DB >> 28753427 |
Rajat M Gupta1, Joseph Hadaya2, Aditi Trehan2, Seyedeh M Zekavat2, Carolina Roselli2, Derek Klarin2, Connor A Emdin2, Catharina R E Hilvering3, Valerio Bianchi3, Christian Mueller4, Amit V Khera5, Russell J H Ryan6, Jesse M Engreitz2, Robbyn Issner2, Noam Shoresh2, Charles B Epstein2, Wouter de Laat3, Jonathan D Brown7, Renate B Schnabel4, Bradley E Bernstein6, Sekar Kathiresan8.
Abstract
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.Entities:
Keywords: SNP; cardiovascular diseases; coronary artery disease; endothelial cells; endothelin-1; epigenomics; genetic enhancer elements; genome-wide association study; hypertension; migraine disorders
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Year: 2017 PMID： 28753427 PMCID： PMC5785707 DOI： 10.1016/j.cell.2017.06.049
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582