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

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.
PMID
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Authors

Mayor MeshTerms

Genetic Predisposition to Disease

Polymorphism, Single Nucleotide

Keywords

SNP

cardiovascular diseases

coronary artery disease

endothelial cells

endothelin-1

epigenomics

genetic enhancer elements

genome-wide association study

hypertension

migraine disorders

Journal Title cell
Publication Year Start




PMID- 28753427
OWN - NLM
STAT- MEDLINE
DA  - 20170728
DCOM- 20170808
LR  - 20170808
IS  - 1097-4172 (Electronic)
IS  - 0092-8674 (Linking)
VI  - 170
IP  - 3
DP  - 2017 Jul 27
TI  - A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of
      Endothelin-1 Gene Expression.
PG  - 522-533.e15
LID - S0092-8674(17)30768-7 [pii]
LID - 10.1016/j.cell.2017.06.049 [doi]
AB  - 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.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Gupta, Rajat M
AU  - Gupta RM
AD  - 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: [email protected]
FAU - Hadaya, Joseph
AU  - Hadaya J
AD  - Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
FAU - Trehan, Aditi
AU  - Trehan A
AD  - Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
FAU - Zekavat, Seyedeh M
AU  - Zekavat SM
AD  - Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
FAU - Roselli, Carolina
AU  - Roselli C
AD  - Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
FAU - Klarin, Derek
AU  - Klarin D
AD  - Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
FAU - Emdin, Connor A
AU  - Emdin CA
AD  - Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
FAU - Hilvering, Catharina R E
AU  - Hilvering CRE
AD  - Hubrecht Institute, University Medical Center Utrecht, Utrecht, the Netherlands.
FAU - Bianchi, Valerio
AU  - Bianchi V
AD  - Hubrecht Institute, University Medical Center Utrecht, Utrecht, the Netherlands.
FAU - Mueller, Christian
AU  - Mueller C
AD  - Department of General and Interventional Cardiology, University Heart Center
      Hamburg-Eppendorf, Hamburg, Germany.
FAU - Khera, Amit V
AU  - Khera AV
AD  - 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.
FAU - Ryan, Russell J H
AU  - Ryan RJH
AD  - Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Department of 
      Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA,
      USA.
FAU - Engreitz, Jesse M
AU  - Engreitz JM
AD  - Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
FAU - Issner, Robbyn
AU  - Issner R
AD  - Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
FAU - Shoresh, Noam
AU  - Shoresh N
AD  - Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
FAU - Epstein, Charles B
AU  - Epstein CB
AD  - Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
FAU - de Laat, Wouter
AU  - de Laat W
AD  - Hubrecht Institute, University Medical Center Utrecht, Utrecht, the Netherlands.
FAU - Brown, Jonathan D
AU  - Brown JD
AD  - Division of Cardiovascular Medicine, Vanderbilt University Medical Center,
      Nashville, TN, USA.
FAU - Schnabel, Renate B
AU  - Schnabel RB
AD  - Department of General and Interventional Cardiology, University Heart Center
      Hamburg-Eppendorf, Hamburg, Germany.
FAU - Bernstein, Bradley E
AU  - Bernstein BE
AD  - Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Department of 
      Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA,
      USA.
FAU - Kathiresan, Sekar
AU  - Kathiresan S
AD  - 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: [email protected]
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
RN  - 0 (Chromatin)
RN  - 0 (Endothelin-1)
RN  - 0 (Histones)
SB  - IM
MH  - Acetylation
MH  - Cells, Cultured
MH  - Chromatin/metabolism
MH  - Chromosome Mapping
MH  - Chromosomes, Human, Pair 6
MH  - Coronary Artery Disease/*genetics
MH  - Endothelial Cells/cytology
MH  - Endothelin-1/blood/*genetics
MH  - Epigenomics
MH  - Gene Editing
MH  - Gene Expression
MH  - *Genetic Predisposition to Disease
MH  - Genome-Wide Association Study
MH  - Histones/metabolism
MH  - Humans
MH  - Muscle, Smooth, Vascular/cytology
MH  - *Polymorphism, Single Nucleotide
MH  - Vascular Diseases/*genetics
OTO - NOTNLM
OT  - SNP
OT  - cardiovascular diseases
OT  - coronary artery disease
OT  - endothelial cells
OT  - endothelin-1
OT  - epigenomics
OT  - genetic enhancer elements
OT  - genome-wide association study
OT  - hypertension
OT  - migraine disorders
EDAT- 2017/07/29 06:00
MHDA- 2017/08/09 06:00
CRDT- 2017/07/29 06:00
PHST- 2016/12/20 [received]
PHST- 2017/04/13 [revised]
PHST- 2017/06/29 [accepted]
AID - S0092-8674(17)30768-7 [pii]
AID - 10.1016/j.cell.2017.06.049 [doi]
PST - ppublish
SO  - Cell. 2017 Jul 27;170(3):522-533.e15. doi: 10.1016/j.cell.2017.06.049.