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

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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; Shoresh, Noam; Epstein, Charles B; de Laat, Wouter; Brown, Jonathan D; Schnabel, Renate B; Bernstein, Bradley E; Kathiresan, Sekar.

in: CELL, Jahrgang 170, Nr. 3, 27.07.2017, S. 522-533.e15.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Gupta, RM, Hadaya, J, Trehan, A, Zekavat, SM, Roselli, C, Klarin, D, Emdin, CA, Hilvering, CRE, Bianchi, V, Mueller, C, Khera, AV, Ryan, RJH, Engreitz, JM, Shoresh, N, Epstein, CB, de Laat, W, Brown, JD, Schnabel, RB, Bernstein, BE & Kathiresan, S 2017, 'A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression', CELL, Jg. 170, Nr. 3, S. 522-533.e15. https://doi.org/10.1016/j.cell.2017.06.049

APA

Gupta, R. M., Hadaya, J., Trehan, A., Zekavat, S. M., Roselli, C., Klarin, D., Emdin, C. A., Hilvering, C. R. E., Bianchi, V., Mueller, C., Khera, A. V., Ryan, R. J. H., Engreitz, J. M., Shoresh, N., Epstein, C. B., de Laat, W., Brown, J. D., Schnabel, R. B., Bernstein, B. E., & Kathiresan, S. (2017). A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression. CELL, 170(3), 522-533.e15. https://doi.org/10.1016/j.cell.2017.06.049

Vancouver

Gupta RM, Hadaya J, Trehan A, Zekavat SM, Roselli C, Klarin D et al. 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. https://doi.org/10.1016/j.cell.2017.06.049

Bibtex

@article{fb5a0f44777d45f1aec69b7a3901729a,
title = "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.",
keywords = "Acetylation, Cells, Cultured, Chromatin/metabolism, Chromosome Mapping, Chromosomes, Human, Pair 6, Coronary Artery Disease/genetics, Endothelial Cells/cytology, Endothelin-1/blood, 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",
author = "Gupta, {Rajat M} and Joseph Hadaya and Aditi Trehan and Zekavat, {Seyedeh M} and Carolina Roselli and Derek Klarin and Emdin, {Connor A} and Hilvering, {Catharina R E} and Valerio Bianchi and Christian Mueller and Khera, {Amit V} and Ryan, {Russell J H} and Engreitz, {Jesse M} and Noam Shoresh and Epstein, {Charles B} and {de Laat}, Wouter and Brown, {Jonathan D} and Schnabel, {Renate B} and Bernstein, {Bradley E} and Sekar Kathiresan",
note = "Copyright {\textcopyright} 2017 Elsevier Inc. All rights reserved.",
year = "2017",
month = jul,
day = "27",
doi = "10.1016/j.cell.2017.06.049",
language = "English",
volume = "170",
pages = "522--533.e15",
journal = "CELL",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",

}

RIS

TY - JOUR

T1 - A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression

AU - Gupta, Rajat M

AU - Hadaya, Joseph

AU - Trehan, Aditi

AU - Zekavat, Seyedeh M

AU - Roselli, Carolina

AU - Klarin, Derek

AU - Emdin, Connor A

AU - Hilvering, Catharina R E

AU - Bianchi, Valerio

AU - Mueller, Christian

AU - Khera, Amit V

AU - Ryan, Russell J H

AU - Engreitz, Jesse M

AU - Shoresh, Noam

AU - Epstein, Charles B

AU - de Laat, Wouter

AU - Brown, Jonathan D

AU - Schnabel, Renate B

AU - Bernstein, Bradley E

AU - Kathiresan, Sekar

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2017/7/27

Y1 - 2017/7/27

N2 - 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.

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.

KW - Acetylation

KW - Cells, Cultured

KW - Chromatin/metabolism

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 6

KW - Coronary Artery Disease/genetics

KW - Endothelial Cells/cytology

KW - Endothelin-1/blood

KW - Epigenomics

KW - Gene Editing

KW - Gene Expression

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Histones/metabolism

KW - Humans

KW - Muscle, Smooth, Vascular/cytology

KW - Polymorphism, Single Nucleotide

KW - Vascular Diseases/genetics

U2 - 10.1016/j.cell.2017.06.049

DO - 10.1016/j.cell.2017.06.049

M3 - SCORING: Journal article

C2 - 28753427

VL - 170

SP - 522-533.e15

JO - CELL

JF - CELL

SN - 0092-8674

IS - 3

ER -