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 BernsteinSekar Kathiresan

Research output: Contribution to journal/periodicalArticleScientificpeer-review

269 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)522-533.e15
Issue number3
Publication statusPublished - 27 Jul 2017


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


Dive into the research topics of 'A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression'. Together they form a unique fingerprint.

Cite this