Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation
CARDIoGRAMPlusC4D; MEGASTROKE; International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group; DISCO register
(2023) Nature Genetics, volume 55, issue 6, pp. 964 - 972
(Article)
Abstract
Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16
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risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.
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Keywords: Genetics
ISSN: 1061-4036
Publisher: Nature Publishing Group
Note: Funding Information: We acknowledge clinical colleagues who referred SCAD cases, patients who supported this research and healthy volunteers included in this study. This study was funded by a European Research Council grant (ERC-Stg-ROSALIND-716628 to N.B.-N.); the French Society of Cardiology, through Fondation Coeur et Recherche (to N.B.-N.); La Fédération Française de Cardiologie (to N.B.-N.); the British Heart Foundation (PG/13/96/30608 to D.A. and SP/16/4/32697 to T.R.W.); the Leicester NIHR Biomedical Research Centre and BeatSCAD charity (to D.A.); the National Health and Medical Research Council (to R.M.G.); the Cardiac Society of Australia and New Zealand Cardiovascular Research Innovation Grant Australia (APP1161200 to R.M.G., D.W.M.M., D.F. and J.C.K.); the New South Wales Health Early-Mid Career Cardiovascular Grant (to E.G.); the New South Wales Health Senior Scientist Cardiovascular Grant (RG194194 to J.C.K.); the New South Wales Health Senior Clinician Cardiovascular Grant (RG193092 to R.M.G.); Bourne Foundation, Agilent and SCAD Research funds (to M.S.T., R.G., S.N.H. and T.M.O.); the National Institutes of Health (T32 GM72474 to T.M.O., R35HL161016 to S.K.G. (who was also supported by R01HL086694 and R01HL139672), R01HL148167 to J.C.K. (to support J.W.O., D.K.-D. and V.d.E.), R01HL147883 to X.Y. and 1K23HL155506 to M.S.T.); the Genome Consortia and Mayo Clinic Center for Individualized Medicine of the Heart and Stroke Foundation of Canada (G-17-0016340 to J.S.); the Canadian Institutes of Health Research (grant 136799 to J.S.); the US Department of Defense; the University of Michigan Frankel Cardiovascular Center M-BRISC program (to S.K.G.); the University of Michigan A. Alfred Taubman Institute (to S.K.G.); a Michael Smith Foundation for Health Research Scholar award (to J.S. and L.R.B.); the FMD Society of America; the American Heart Association (pre-doctoral fellowship 829009 to M.B.); and the UCLA Integrative Biology and Physiology Edith Hyde fellowship (to M.B.). Genotyping of DISCO and SCAD-UK II patients was performed in a platform supported by the Spanish National Cancer Research Centre, at the Human Genotyping laboratory, a member of the CeGen Biomolecular resources platform (PRB3), supported by grant PT17/0019, of the PE I + D + i 2013–2016, funded by Instituto de Salud Carlos III and the European Regional Development Fund. Fondation Alzheimer supported genotyping of the 3C study (Paris, France) to P.A. We thank AstraZeneca’s Centre for Genomics Research (Discovery Sciences, BioPharmaceuticals R&D) for funding the sequencing of participants in cohort SCAD-UK I and providing bioinformatics support. We acknowledge the leadership of the ESC-ACVC SCAD Study Group. The DISCO investigators thank the French Society of Cardiology and French Coronary Atheroma and Interventional Cardiology Group for support, as well as clinical research associates of the Clermont-Ferrand University Hospital: E. Chazot, C. Bellanger, L. Cubizolles, A. Thalamy and O. Lamallem. The SCAD-UK study investigators acknowledge J. Middleton, J. Plume, D. Alexander, D. Lawday and A. Marshall for support with SCAD research, as well as the Research Analytics and Informatics team at AstraZeneca’s Centre for Genomics for processing and analyzing sequencing data. The VCCRI study investigators thank C. M. Y. Wong, K. Mishra and R. Johnson for contributions to data collection and sample processing, as well as the Medical Genome Reference Bank, including the 45 and Up and ASPREE study patients who were controls for this study. The CanSCAD/MGI study investigators acknowledge the University of Michigan Precision Health Initiative and Medical School Central Biorepository for providing biospecimen storage, management, processing and distribution services, as well as the Center for Statistical Genetics in the Department of Biostatistics at the School of Public Health for genotype data management in support of this research. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgements.html . The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, as well as by the National Cancer Institute, National Human Genome Research Institute, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health and National Institute of Neurological Disorders and Stroke. We acknowledge the FMD Society of America and Vancouver SCAD Conference organizers for enabling study enrollments at patient meetings. Funding Information: We acknowledge clinical colleagues who referred SCAD cases, patients who supported this research and healthy volunteers included in this study. This study was funded by a European Research Council grant (ERC-Stg-ROSALIND-716628 to N.B.-N.); the French Society of Cardiology, through Fondation Coeur et Recherche (to N.B.-N.); La Fédération Française de Cardiologie (to N.B.-N.); the British Heart Foundation (PG/13/96/30608 to D.A. and SP/16/4/32697 to T.R.W.); the Leicester NIHR Biomedical Research Centre and BeatSCAD charity (to D.A.); the National Health and Medical Research Council (to R.M.G.); the Cardiac Society of Australia and New Zealand Cardiovascular Research Innovation Grant Australia (APP1161200 to R.M.G., D.W.M.M., D.F. and J.C.K.); the New South Wales Health Early-Mid Career Cardiovascular Grant (to E.G.); the New South Wales Health Senior Scientist Cardiovascular Grant (RG194194 to J.C.K.); the New South Wales Health Senior Clinician Cardiovascular Grant (RG193092 to R.M.G.); Bourne Foundation, Agilent and SCAD Research funds (to M.S.T., R.G., S.N.H. and T.M.O.); the National Institutes of Health (T32 GM72474 to T.M.O., R35HL161016 to S.K.G. (who was also supported by R01HL086694 and R01HL139672), R01HL148167 to J.C.K. (to support J.W.O., D.K.-D. and V.d.E.), R01HL147883 to X.Y. and 1K23HL155506 to M.S.T.); the Genome Consortia and Mayo Clinic Center for Individualized Medicine of the Heart and Stroke Foundation of Canada (G-17-0016340 to J.S.); the Canadian Institutes of Health Research (grant 136799 to J.S.); the US Department of Defense; the University of Michigan Frankel Cardiovascular Center M-BRISC program (to S.K.G.); the University of Michigan A. Alfred Taubman Institute (to S.K.G.); a Michael Smith Foundation for Health Research Scholar award (to J.S. and L.R.B.); the FMD Society of America; the American Heart Association (pre-doctoral fellowship 829009 to M.B.); and the UCLA Integrative Biology and Physiology Edith Hyde fellowship (to M.B.). Genotyping of DISCO and SCAD-UK II patients was performed in a platform supported by the Spanish National Cancer Research Centre, at the Human Genotyping laboratory, a member of the CeGen Biomolecular resources platform (PRB3), supported by grant PT17/0019, of the PE I + D + i 2013–2016, funded by Instituto de Salud Carlos III and the European Regional Development Fund. Fondation Alzheimer supported genotyping of the 3C study (Paris, France) to P.A. We thank AstraZeneca’s Centre for Genomics Research (Discovery Sciences, BioPharmaceuticals R&D) for funding the sequencing of participants in cohort SCAD-UK I and providing bioinformatics support. We acknowledge the leadership of the ESC-ACVC SCAD Study Group. The DISCO investigators thank the French Society of Cardiology and French Coronary Atheroma and Interventional Cardiology Group for support, as well as clinical research associates of the Clermont-Ferrand University Hospital: E. Chazot, C. Bellanger, L. Cubizolles, A. Thalamy and O. Lamallem. The SCAD-UK study investigators acknowledge J. Middleton, J. Plume, D. Alexander, D. Lawday and A. Marshall for support with SCAD research, as well as the Research Analytics and Informatics team at AstraZeneca’s Centre for Genomics for processing and analyzing sequencing data. The VCCRI study investigators thank C. M. Y. Wong, K. Mishra and R. Johnson for contributions to data collection and sample processing, as well as the Medical Genome Reference Bank, including the 45 and Up and ASPREE study patients who were controls for this study. The CanSCAD/MGI study investigators acknowledge the University of Michigan Precision Health Initiative and Medical School Central Biorepository for providing biospecimen storage, management, processing and distribution services, as well as the Center for Statistical Genetics in the Department of Biostatistics at the School of Public Health for genotype data management in support of this research. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgements.html. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, as well as by the National Cancer Institute, National Human Genome Research Institute, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health and National Institute of Neurological Disorders and Stroke. We acknowledge the FMD Society of America and Vancouver SCAD Conference organizers for enabling study enrollments at patient meetings. Funding Information: D.A. has received kind support from AstraZeneca (for gene sequencing in patients with SCAD) and grant funding from AstraZeneca for unrelated research. He has also received research funding from Abbott Vascular to support a clinical research fellow and has undertaken consultancy for General Electric to support research funds. He holds unrelated patents EP3277337A1 and PCT/GB2017/050877. The remaining authors declare no competing interests. Publisher Copyright: © 2023, The Author(s).
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