A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression
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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; Shoresh, Noam; Epstein, Charles B; de Laat, Wouter; Brown, Jonathan D; Schnabel, Renate B; Bernstein, Bradley E; Kathiresan, Sekar.
In: CELL, Vol. 170, No. 3, 27.07.2017, p. 522-533.e15.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression
AU - Gupta, Rajat M
AU - Hadaya, Joseph
AU - Trehan, Aditi
AU - Zekavat, Seyedeh M
AU - Roselli, Carolina
AU - Klarin, Derek
AU - Emdin, Connor A
AU - Hilvering, Catharina R E
AU - Bianchi, Valerio
AU - Mueller, Christian
AU - Khera, Amit V
AU - Ryan, Russell J H
AU - Engreitz, Jesse M
AU - Shoresh, Noam
AU - Epstein, Charles B
AU - de Laat, Wouter
AU - Brown, Jonathan D
AU - Schnabel, Renate B
AU - Bernstein, Bradley E
AU - Kathiresan, Sekar
N1 - Copyright © 2017 Elsevier Inc. All rights reserved.
PY - 2017/7/27
Y1 - 2017/7/27
N2 - 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.
AB - 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.
KW - Acetylation
KW - Cells, Cultured
KW - Chromatin/metabolism
KW - Chromosome Mapping
KW - Chromosomes, Human, Pair 6
KW - Coronary Artery Disease/genetics
KW - Endothelial Cells/cytology
KW - Endothelin-1/blood
KW - Epigenomics
KW - Gene Editing
KW - Gene Expression
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Histones/metabolism
KW - Humans
KW - Muscle, Smooth, Vascular/cytology
KW - Polymorphism, Single Nucleotide
KW - Vascular Diseases/genetics
U2 - 10.1016/j.cell.2017.06.049
DO - 10.1016/j.cell.2017.06.049
M3 - SCORING: Journal article
C2 - 28753427
VL - 170
SP - 522-533.e15
JO - CELL
JF - CELL
SN - 0092-8674
IS - 3
ER -