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

David Adlam; Timothy M. Olson; CARDIoGRAMPlusC4D Study Group; DISCO Consortium; Nicolas Combaret; Jason C. Kovacic; Abtehale Al-Hussaini; Megan M. O'Byrne; Sara Bouajila; Adrien Georges; Ketan Mishra; Peter S. Braund; Valentina d'Escamard; Marios Margaritis; Christopher P. Nelson; Mariza de Andrade; Daniella Kadian-Dodov; Catherine A. Welch; Stephani Mazurkiewicz; Xavier Jeunemaitre; Abbas Dehghan; Markus Scholz; Andre Uitterlinden; Wei Zhao; Paul S. de Vries; Albert Hofman

doi:10.1016/j.jacc.2018.09.085

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

David Adlam, Timothy M. Olson, CARDIoGRAMPlusC4D Study Group, DISCO Consortium, Nicolas Combaret, Jason C. Kovacic, Abtehale Al-Hussaini, Megan M. O'Byrne, Sara Bouajila, Adrien Georges, Ketan Mishra, Peter S. Braund, Valentina d'Escamard, Marios Margaritis, Christopher P. Nelson, Mariza de Andrade, Daniella Kadian-Dodov, Catherine A. Welch, Stephani Mazurkiewicz, Xavier JeunemaitreAbbas Dehghan, Markus Scholz, Andre Uitterlinden, Wei Zhao, Paul S. de Vries, Albert Hofman

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

149 Citations (Scopus)

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.

Original language	English
Pages (from-to)	58-66
Number of pages	9
Journal	Journal of the American College of Cardiology
Volume	73
Issue number	1
DOIs	https://doi.org/10.1016/j.jacc.2018.09.085
Publication status	Published - 8 Jan 2019

Bibliographical note

Funding Information:
The authors thank our clinical colleagues throughout Europe, Australia, and the United States who referred SCAD cases to our research studies, and our patients who supported this research. The authors also thank all clinicians who contributed to the DISCO (Etude de la prévalence de la dysplasie fibromusculaire chez les patients présentant une DISsection Coronaire) register. The U.K. SCAD study specifically acknowledges Ellie Clarke, Jenny Middleton, Martin Batty, Emma Beeston, and Tara Maitland for their support of SCAD research. The authors acknowledge the leadership of the ESC-ACCA (European Society of Cardiology-Acute Cardiovascular Care Association) SCAD study group and the support of SCAD survivors. The Australian SCAD study specifically acknowledges support from Pamela McKenzie and Sarah Ford, President, SCAD Research Inc., Australia.

Funding Information:
The French SCAD study was supported by the French Society of Cardiology foundation, Coeur et recherche, the French Coronary Atheroma and Interventional Cardiology Group, and European Research Council grant ERC-Stg-ROSALIND-716628 to Dr. Bouatia-Naji. The U.K. SCAD study was supported by the British Heart Foundation and National Institute for Health Research rare disease translational collaboration, the Leicester NIHR Biomedical Research Centre, and BeatSCAD. The Mount Sinai DEFINE-FMD study was supported by a philanthropic gift. The Australian study was supported by National Health and Medical Research Council of Australia grant 1074386, the Cardiac Society of Australia and New Zealand, St. Vincent’s Clinic Foundation, the Catholic Archdiocese of Sydney, and SCAD Research Inc., Australia. The Mayo Clinic SCAD study was supported by SCAD Research, Inc., the Department of Cardiovascular Medicine, Mayo Clinic, and the National Institutes of Health “Building Interdisciplinary Research Careers in Women's Health” program grant NH HD 65987 to Dr. Tweet. Dr. Adlam has received research funding from Abbott Vascular Inc. and AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Publisher Copyright:
© 2019 American College of Cardiology Foundation

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10.1016/j.jacc.2018.09.085

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Adlam, D., Olson, T. M., CARDIoGRAMPlusC4D Study Group, DISCO Consortium, Combaret, N., Kovacic, J. C., Al-Hussaini, A., O'Byrne, M. M., Bouajila, S., Georges, A., Mishra, K., Braund, P. S., d'Escamard, V., Margaritis, M., Nelson, C. P., de Andrade, M., Kadian-Dodov, D., Welch, C. A., Mazurkiewicz, S., ... Hofman, A. (2019). Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection. Journal of the American College of Cardiology, 73(1), 58-66. https://doi.org/10.1016/j.jacc.2018.09.085

@article{e68967ea374a444cbd315a9e71f42f30,

title = "Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection",

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.",

author = "David Adlam and Olson, {Timothy M.} and {CARDIoGRAMPlusC4D Study Group} and {DISCO Consortium} 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 Abbas Dehghan and Markus Scholz and Andre Uitterlinden and Wei Zhao and {de Vries}, {Paul S.} and Albert Hofman",

note = "Funding Information: The authors thank our clinical colleagues throughout Europe, Australia, and the United States who referred SCAD cases to our research studies, and our patients who supported this research. The authors also thank all clinicians who contributed to the DISCO (Etude de la pr{\'e}valence de la dysplasie fibromusculaire chez les patients pr{\'e}sentant une DISsection Coronaire) register. The U.K. SCAD study specifically acknowledges Ellie Clarke, Jenny Middleton, Martin Batty, Emma Beeston, and Tara Maitland for their support of SCAD research. The authors acknowledge the leadership of the ESC-ACCA (European Society of Cardiology-Acute Cardiovascular Care Association) SCAD study group and the support of SCAD survivors. The Australian SCAD study specifically acknowledges support from Pamela McKenzie and Sarah Ford, President, SCAD Research Inc., Australia. Funding Information: The French SCAD study was supported by the French Society of Cardiology foundation, Coeur et recherche, the French Coronary Atheroma and Interventional Cardiology Group, and European Research Council grant ERC-Stg-ROSALIND-716628 to Dr. Bouatia-Naji. The U.K. SCAD study was supported by the British Heart Foundation and National Institute for Health Research rare disease translational collaboration, the Leicester NIHR Biomedical Research Centre, and BeatSCAD. The Mount Sinai DEFINE-FMD study was supported by a philanthropic gift. The Australian study was supported by National Health and Medical Research Council of Australia grant 1074386, the Cardiac Society of Australia and New Zealand, St. Vincent{\textquoteright}s Clinic Foundation, the Catholic Archdiocese of Sydney, and SCAD Research Inc., Australia. The Mayo Clinic SCAD study was supported by SCAD Research, Inc., the Department of Cardiovascular Medicine, Mayo Clinic, and the National Institutes of Health “Building Interdisciplinary Research Careers in Women's Health” program grant NH HD 65987 to Dr. Tweet. Dr. Adlam has received research funding from Abbott Vascular Inc. and AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Publisher Copyright: {\textcopyright} 2019 American College of Cardiology Foundation",

year = "2019",

month = jan,

day = "8",

doi = "10.1016/j.jacc.2018.09.085",

language = "English",

volume = "73",

pages = "58--66",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier Inc.",

number = "1",

}

Adlam, D, Olson, TM, CARDIoGRAMPlusC4D Study Group, DISCO Consortium, Combaret, N, Kovacic, JC, Al-Hussaini, A, O'Byrne, MM, Bouajila, S, Georges, A, Mishra, K, Braund, PS, d'Escamard, V, Margaritis, M, Nelson, CP, de Andrade, M, Kadian-Dodov, D, Welch, CA, Mazurkiewicz, S, Jeunemaitre, X, Dehghan, A, Scholz, M, Uitterlinden, A, Zhao, W, de Vries, PS & Hofman, A 2019, 'Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection', Journal of the American College of Cardiology, vol. 73, no. 1, pp. 58-66. https://doi.org/10.1016/j.jacc.2018.09.085

TY - JOUR

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

AU - Adlam, David

AU - Olson, Timothy M.

AU - CARDIoGRAMPlusC4D Study Group

AU - DISCO Consortium

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 - Dehghan, Abbas

AU - Scholz, Markus

AU - Uitterlinden, Andre

AU - Zhao, Wei

AU - de Vries, Paul S.

AU - Hofman, Albert

N1 - Funding Information: The authors thank our clinical colleagues throughout Europe, Australia, and the United States who referred SCAD cases to our research studies, and our patients who supported this research. The authors also thank all clinicians who contributed to the DISCO (Etude de la prévalence de la dysplasie fibromusculaire chez les patients présentant une DISsection Coronaire) register. The U.K. SCAD study specifically acknowledges Ellie Clarke, Jenny Middleton, Martin Batty, Emma Beeston, and Tara Maitland for their support of SCAD research. The authors acknowledge the leadership of the ESC-ACCA (European Society of Cardiology-Acute Cardiovascular Care Association) SCAD study group and the support of SCAD survivors. The Australian SCAD study specifically acknowledges support from Pamela McKenzie and Sarah Ford, President, SCAD Research Inc., Australia. Funding Information: The French SCAD study was supported by the French Society of Cardiology foundation, Coeur et recherche, the French Coronary Atheroma and Interventional Cardiology Group, and European Research Council grant ERC-Stg-ROSALIND-716628 to Dr. Bouatia-Naji. The U.K. SCAD study was supported by the British Heart Foundation and National Institute for Health Research rare disease translational collaboration, the Leicester NIHR Biomedical Research Centre, and BeatSCAD. The Mount Sinai DEFINE-FMD study was supported by a philanthropic gift. The Australian study was supported by National Health and Medical Research Council of Australia grant 1074386, the Cardiac Society of Australia and New Zealand, St. Vincent’s Clinic Foundation, the Catholic Archdiocese of Sydney, and SCAD Research Inc., Australia. The Mayo Clinic SCAD study was supported by SCAD Research, Inc., the Department of Cardiovascular Medicine, Mayo Clinic, and the National Institutes of Health “Building Interdisciplinary Research Careers in Women's Health” program grant NH HD 65987 to Dr. Tweet. Dr. Adlam has received research funding from Abbott Vascular Inc. and AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Publisher Copyright: © 2019 American College of Cardiology Foundation

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.

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U2 - 10.1016/j.jacc.2018.09.085

DO - 10.1016/j.jacc.2018.09.085

M3 - Article

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SN - 0735-1097

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JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

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

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