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

DISCO Consortium, CARDIoGRAMPlusC4D Study Group

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73 Citations (Scopus)


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 languageEnglish
Pages (from-to)58-66
Number of pages9
JournalJournal of the American College of Cardiology
Issue number1
Publication statusPublished - 8 Jan 2019
Externally publishedYes

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


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


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