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

Rajat M Gupta; Joseph Hadaya; Aditi Trehan; Seyedeh M Zekavat; Carolina Roselli; Derek Klarin; Connor A Emdin; Catharina R E Hilvering; Valerio Bianchi; Christian Mueller; Amit V Khera; Russell J H Ryan; Jesse M Engreitz; Robbyn Issner; Noam Shoresh; Charles B Epstein; Wouter de Laat; Jonathan D Brown; Renate B Schnabel; Bradley E Bernstein; Sekar Kathiresan

doi:10.1016/j.cell.2017.06.049

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

Cell. 2017 Jul 27;170(3):522-533.e15. doi: 10.1016/j.cell.2017.06.049.

Authors

Rajat M Gupta¹, Joseph Hadaya², Aditi Trehan², Seyedeh M Zekavat², Carolina Roselli², Derek Klarin², Connor A Emdin², Catharina R E Hilvering³, Valerio Bianchi³, Christian Mueller⁴, Amit V Khera⁵, Russell J H Ryan⁶, Jesse M Engreitz², Robbyn Issner², Noam Shoresh², Charles B Epstein², Wouter de Laat³, Jonathan D Brown⁷, Renate B Schnabel⁴, Bradley E Bernstein⁶, Sekar Kathiresan⁸

Affiliations

¹ 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, Boston, MA, USA. Electronic address: rgupta@broadinstitute.org.
² Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
³ Hubrecht Institute, University Medical Center Utrecht, Utrecht, the Netherlands.
⁴ Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany.
⁵ 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, Boston, MA, USA.
⁶ Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ 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, Boston, MA, USA. Electronic address: skathiresan1@mgh.harvard.edu.

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.

Keywords: SNP; cardiovascular diseases; coronary artery disease; endothelial cells; endothelin-1; epigenomics; genetic enhancer elements; genome-wide association study; hypertension; migraine disorders.

MeSH terms

Acetylation
Cells, Cultured
Chromatin / metabolism
Chromosome Mapping
Chromosomes, Human, Pair 6
Coronary Artery Disease / genetics*
Endothelial Cells / cytology
Endothelin-1 / blood
Endothelin-1 / genetics*
Epigenomics
Gene Editing
Gene Expression
Genetic Predisposition to Disease*
Genome-Wide Association Study
Histones / metabolism
Humans
Muscle, Smooth, Vascular / cytology
Polymorphism, Single Nucleotide*
Vascular Diseases / genetics*

Substances

Chromatin
Endothelin-1
Histones

Abstract

MeSH terms

Substances

Grants and funding