A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression
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
(2017) Cell, volume 170, issue 3, pp. 522 - 533.e15
(Article)
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
... read more
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.
show less
Download/Full Text
The full text of this publication is not available.
Keywords: cardiovascular diseases, coronary artery disease, endothelial cells, endothelin-1, epigenomics, genetic enhancer elements, genome-wide association study, hypertension, migraine disorders, SNP, General Biochemistry,Genetics and Molecular Biology, Journal Article
ISSN: 0092-8674
Publisher: Cell Press
Note: Funding Information: This work was supported by a Sarnoff Scholar Award, a Harvard Catalyst CMERIT Award, and NIH NHLBI K08-HL128810 (to R.M.G.); NIH T32 HL007734 (to D.K.); NIH NHGRI U54HG006991 to B.E.B.; and NIH NIDDK R01 DK097768, Fondation Leducq CVGeneF(x) Transatlantic Network of Excellence, NIH R01HL127564, and the Ofer and Shelly Nemirovsky MGH Research Scholar Award (to S.K.). The CHARGE endothelial function working group provided data for FMD analysis. S.K. reports receiving grants from Bayer Healthcare, Amarin, and Regeneron; serving on scientific advisory boards for Catabasis, Regeneron Genetics Center, Merck, Celera, and Genomics PLC; receiving consulting fees from Novartis, Sanofi, AstraZeneca, Alnylam, Eli Lilly, Lerink Partners, Noble Insights, Merck, Quest Diagnostics, Amgen, Genentech, Corvidia, Ionis Pharmaceuticals, and Eli Lilly; and holding equity in Catabasis and San Therapeutics. Publisher Copyright: © 2017 Elsevier Inc.
(Peer reviewed)