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

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

^*Corresponding author for this work

Cancer

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	522-533.e15
Journal	Cell
Volume	170
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2017.06.049
Publication status	Published - 27 Jul 2017

Keywords

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

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10.1016/j.cell.2017.06.049

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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., Issner, R., Shoresh, N., Epstein, C. B., de Laat, W., Brown, J. D., Schnabel, R. B., ... 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

@article{da6f18d1f57a4158af6cc5abbc2fd2e1,

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 = "cardiovascular diseases, coronary artery disease, endothelial cells, endothelin-1, epigenomics, genetic enhancer elements, genome-wide association study, hypertension, migraine disorders, SNP",

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 Robbyn Issner 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 = "Funding Information: This work was supported by a Sarnoff Scholar Award, a Harvard Catalyst CMERIT Award, and NIH NHLBI K08-HL128810 (to R.M.G.); NIH T32 HL007734 (to D.K.); NIH NHGRI U54HG006991 to B.E.B.; and NIH NIDDK R01 DK097768, Fondation Leducq CVGeneF(x) Transatlantic Network of Excellence, NIH R01HL127564, and the Ofer and Shelly Nemirovsky MGH Research Scholar Award (to S.K.). The CHARGE endothelial function working group provided data for FMD analysis. S.K. reports receiving grants from Bayer Healthcare, Amarin, and Regeneron; serving on scientific advisory boards for Catabasis, Regeneron Genetics Center, Merck, Celera, and Genomics PLC; receiving consulting fees from Novartis, Sanofi, AstraZeneca, Alnylam, Eli Lilly, Lerink Partners, Noble Insights, Merck, Quest Diagnostics, Amgen, Genentech, Corvidia, Ionis Pharmaceuticals, and Eli Lilly; and holding equity in Catabasis and San Therapeutics. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = jul,

day = "27",

doi = "10.1016/j.cell.2017.06.049",

language = "English",

volume = "170",

pages = "522--533.e15",

number = "3",

}

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, Issner, R, 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, vol. 170, no. 3, pp. 522-533.e15. https://doi.org/10.1016/j.cell.2017.06.049

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 - Issner, Robbyn

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 - Funding Information: This work was supported by a Sarnoff Scholar Award, a Harvard Catalyst CMERIT Award, and NIH NHLBI K08-HL128810 (to R.M.G.); NIH T32 HL007734 (to D.K.); NIH NHGRI U54HG006991 to B.E.B.; and NIH NIDDK R01 DK097768, Fondation Leducq CVGeneF(x) Transatlantic Network of Excellence, NIH R01HL127564, and the Ofer and Shelly Nemirovsky MGH Research Scholar Award (to S.K.). The CHARGE endothelial function working group provided data for FMD analysis. S.K. reports receiving grants from Bayer Healthcare, Amarin, and Regeneron; serving on scientific advisory boards for Catabasis, Regeneron Genetics Center, Merck, Celera, and Genomics PLC; receiving consulting fees from Novartis, Sanofi, AstraZeneca, Alnylam, Eli Lilly, Lerink Partners, Noble Insights, Merck, Quest Diagnostics, Amgen, Genentech, Corvidia, Ionis Pharmaceuticals, and Eli Lilly; and holding equity in Catabasis and San Therapeutics. Publisher Copyright: © 2017 Elsevier Inc.

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 - cardiovascular diseases

KW - coronary artery disease

KW - endothelial cells

KW - endothelin-1

KW - epigenomics

KW - genetic enhancer elements

KW - genome-wide association study

KW - hypertension

KW - migraine disorders

KW - SNP

UR - http://www.scopus.com/inward/record.url?scp=85026362170&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2017.06.049

DO - 10.1016/j.cell.2017.06.049

M3 - Article

C2 - 28753427

AN - SCOPUS:85026362170

SN - 0092-8674

VL - 170

SP - 522-533.e15

JO - Cell

JF - Cell

IS - 3

ER -

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

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Keywords

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