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

Cell
Authors
Keywords
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.

Year of Publication
2017
Journal
Cell
Volume
170
Issue
3
Pages
522-533.e15
Date Published
2017 Jul 27
ISSN
1097-4172
DOI
10.1016/j.cell.2017.06.049
PubMed ID
28753427
PubMed Central ID
PMC5785707
Links
Grant list
K08 HL128810 / HL / NHLBI NIH HHS / United States
U54 HG006991 / HG / NHGRI NIH HHS / United States
L30 HL120024 / HL / NHLBI NIH HHS / United States
T32 HL007734 / HL / NHLBI NIH HHS / United States
R01 HL127564 / HL / NHLBI NIH HHS / United States
UM1 HG009390 / HG / NHGRI NIH HHS / United States
R01 DK097768 / DK / NIDDK NIH HHS / United States