Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection

DISCO Consortium, CARDIoGRAMPlusC4D Study Group, David Adlam, Timothy M. Olson, Nicolas Combaret, Jason C. Kovacic, Siiri E. Iismaa, Abtehale Al-Hussaini, Megan M. O'Byrne, Sara Bouajila, Adrien Georges, Ketan Mishra, Peter S. Braund, Valentina d'Escamard, Siying Huang, Marios Margaritis, Christopher P. Nelson, Mariza de Andrade, Daniella Kadian-Dodov, Catherine A. Welch & 32 others Stephani Mazurkiewicz, Xavier Jeunemaitre, Pascal Motreff, Loïc Belle, Patrick Dupouy, Pierre Barnay, Nicolas Meneveau, Martine Gilard, Gilles Rioufol, Grégoire Range, Philippe Brunel, Nicolas Delarche, Emmanuelle Filippi, Louis Le Bivic, Brahim Harbaoui, Hakim Benamer, Guillaume Cayla, Olivier Varenne, Stephane Peggy Manzo-Silberman, Johanne Silvain, Christian Spaulding, Christophe Caussin, Edouard Gerbaud, Yann Valy, René Koning, Thibault Lhermusier, Stanislas Champin, Emmanuel Salengro, Arnaud Fluttaz, Amer Zabalawi, Alanna C Morrison, Eric Boerwinkle

Research output: Contribution to journalArticle

  • 1 Citations

Abstract

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. Objectives: This study sought to test the association between the rs9349379 genotype and SCAD. Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

LanguageEnglish
Pages58-66
Number of pages9
JournalJournal of the American College of Cardiology
Volume73
Issue number1
DOIs
StatePublished - Jan 8 2019

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Genetic Loci
Endothelin-1
Fibromuscular Dysplasia
Odds Ratio
Confidence Intervals
Spontaneous Coronary Artery Dissection
Genotype
Pregnancy
Acute Coronary Syndrome
Vascular Diseases
France
Observational Studies
Blood Vessels
Meta-Analysis
Case-Control Studies
Coronary Artery Disease
Atherosclerosis
Alleles

Keywords

  • cardiovascular disease in women
  • fibromuscular dysplasia
  • genetic association
  • myocardial infarction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection. / DISCO Consortium; CARDIoGRAMPlusC4D Study Group.

In: Journal of the American College of Cardiology, Vol. 73, No. 1, 08.01.2019, p. 58-66.

Research output: Contribution to journalArticle

DISCO Consortium ; CARDIoGRAMPlusC4D Study Group. / Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection. In: Journal of the American College of Cardiology. 2019 ; Vol. 73, No. 1. pp. 58-66.
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abstract = "Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. Objectives: This study sought to test the association between the rs9349379 genotype and SCAD. Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95{\%} confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95{\%} CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95{\%} CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.",
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author = "{DISCO Consortium} and {CARDIoGRAMPlusC4D Study Group} and David Adlam and Olson, {Timothy M.} and Nicolas Combaret and Kovacic, {Jason C.} and Iismaa, {Siiri E.} and Abtehale Al-Hussaini and O'Byrne, {Megan M.} and Sara Bouajila and Adrien Georges and Ketan Mishra and Braund, {Peter S.} and Valentina d'Escamard and Siying Huang and Marios Margaritis and Nelson, {Christopher P.} and {de Andrade}, Mariza and Daniella Kadian-Dodov and Welch, {Catherine A.} and Stephani Mazurkiewicz and Xavier Jeunemaitre and Pascal Motreff and Lo{\"i}c Belle and Patrick Dupouy and Pierre Barnay and Nicolas Meneveau and Martine Gilard and Gilles Rioufol and Gr{\'e}goire Range and Philippe Brunel and Nicolas Delarche and Emmanuelle Filippi and {Le Bivic}, Louis and Brahim Harbaoui and Hakim Benamer and Guillaume Cayla and Olivier Varenne and Manzo-Silberman, {Stephane Peggy} and Johanne Silvain and Christian Spaulding and Christophe Caussin and Edouard Gerbaud and Yann Valy and Ren{\'e} Koning and Thibault Lhermusier and Stanislas Champin and Emmanuel Salengro and Arnaud Fluttaz and Amer Zabalawi and Morrison, {Alanna C} and Eric Boerwinkle",
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TY - JOUR

T1 - Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection

AU - DISCO Consortium

AU - CARDIoGRAMPlusC4D Study Group

AU - Adlam, David

AU - Olson, Timothy M.

AU - Combaret, Nicolas

AU - Kovacic, Jason C.

AU - Iismaa, Siiri E.

AU - Al-Hussaini, Abtehale

AU - O'Byrne, Megan M.

AU - Bouajila, Sara

AU - Georges, Adrien

AU - Mishra, Ketan

AU - Braund, Peter S.

AU - d'Escamard, Valentina

AU - Huang, Siying

AU - Margaritis, Marios

AU - Nelson, Christopher P.

AU - de Andrade, Mariza

AU - Kadian-Dodov, Daniella

AU - Welch, Catherine A.

AU - Mazurkiewicz, Stephani

AU - Jeunemaitre, Xavier

AU - Motreff, Pascal

AU - Belle, Loïc

AU - Dupouy, Patrick

AU - Barnay, Pierre

AU - Meneveau, Nicolas

AU - Gilard, Martine

AU - Rioufol, Gilles

AU - Range, Grégoire

AU - Brunel, Philippe

AU - Delarche, Nicolas

AU - Filippi, Emmanuelle

AU - Le Bivic, Louis

AU - Harbaoui, Brahim

AU - Benamer, Hakim

AU - Cayla, Guillaume

AU - Varenne, Olivier

AU - Manzo-Silberman, Stephane Peggy

AU - Silvain, Johanne

AU - Spaulding, Christian

AU - Caussin, Christophe

AU - Gerbaud, Edouard

AU - Valy, Yann

AU - Koning, René

AU - Lhermusier, Thibault

AU - Champin, Stanislas

AU - Salengro, Emmanuel

AU - Fluttaz, Arnaud

AU - Zabalawi, Amer

AU - Morrison, Alanna C

AU - Boerwinkle, Eric

PY - 2019/1/8

Y1 - 2019/1/8

N2 - Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. Objectives: This study sought to test the association between the rs9349379 genotype and SCAD. Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

AB - Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. Objectives: This study sought to test the association between the rs9349379 genotype and SCAD. Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

KW - cardiovascular disease in women

KW - fibromuscular dysplasia

KW - genetic association

KW - myocardial infarction

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