期刊
CELL
卷 170, 期 3, 页码 522-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2017.06.049
关键词
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资金
- Sarnoff Scholar Award
- Harvard Catalyst CMERIT Award
- NIH NHLBI [K08-HL128810]
- NIH [T32 HL007734, R01HL127564]
- NIH NHGRI [U54HG006991]
- NIH NIDDK [R01 DK097768]
- Fondation Leducq CVGeneF(x) Transatlantic Network of Excellence
- Ofer and Shelly Nemirovsky MGH Research Scholar Award
- Bayer Healthcare
- Amarin
- Regeneron
- Novartis
- Sanofi
- AstraZeneca
- Alnylam
- Eli Lilly
- Lerink Partners
- Noble Insights
- Merck
- Quest Diagnostics
- Amgen
- Genentech
- Corvidia
- Ionis Pharmaceuticals
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.
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