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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; Issner, Robbyn; Shoresh, Noam; Epstein, Charles B; de Laat, Wouter; Brown, Jonathan D; Schnabel, Renate B; Bernstein, Bradley E; Kathiresan, Sekar.
Affiliation
  • Gupta RM; Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, B
  • Hadaya J; Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
  • Trehan A; Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
  • Zekavat SM; Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
  • Roselli C; Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
  • Klarin D; Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
  • Emdin CA; Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
  • Hilvering CRE; Hubrecht Institute, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Bianchi V; Hubrecht Institute, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Mueller C; Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany.
  • Khera AV; Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, B
  • Ryan RJH; Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Engreitz JM; Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
  • Issner R; Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
  • Shoresh N; Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
  • Epstein CB; Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
  • de Laat W; Hubrecht Institute, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Brown JD; Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Schnabel RB; Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany.
  • Bernstein BE; Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Kathiresan S; Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, B
Cell ; 170(3): 522-533.e15, 2017 Jul 27.
Article in En | MEDLINE | ID: mdl-28753427
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Vascular Diseases / Coronary Artery Disease / Endothelin-1 / Genetic Predisposition to Disease / Polymorphism, Single Nucleotide Type of study: Risk_factors_studies Limits: Humans Language: En Journal: Cell Year: 2017 Document type: Article Country of publication: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Vascular Diseases / Coronary Artery Disease / Endothelin-1 / Genetic Predisposition to Disease / Polymorphism, Single Nucleotide Type of study: Risk_factors_studies Limits: Humans Language: En Journal: Cell Year: 2017 Document type: Article Country of publication: Estados Unidos