Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation
David Adlam, Takiy-Eddine Berrandou, Adrien Georges, Christopher P Nelson, Eleni Giannoulatou, Joséphine Henry, Lijiang Ma, Montgomery Blencowe, Tamiel N Turley, Min-Lee Yang, Sandesh Chopade, Chris Finan, Peter S Braund, Ines Sadeg-Sayoud, Siiri E Iismaa, Matthew L Kosel, Xiang Zhou, Stephen E Hamby, Jenny Cheng, Lu Liu, Ingrid Tarr, David W M Muller, Valentina d'Escamard, Annette King, Liam R Brunham, Ania A Baranowska-Clarke, Stéphanie Debette, Philippe Amouyel, Jeffrey W Olin, Snehal Patil, Stephanie E Hesselson, Keerat Junday, Stavroula Kanoni, Krishna G Aragam, Adam S Butterworth, CARDIoGRAMPlusC4D, MEGASTROKE, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, Marysia S Tweet, Rajiv Gulati, Nicolas Combaret, DISCO register, Daniella Kadian-Dodov, Jonathan M Kalman, Diane Fatkin, Aroon D Hingorani, Jacqueline Saw, Tom R Webb, Sharonne N Hayes, Xia Yang, Santhi K Ganesh, Timothy M Olson, Jason C Kovacic, Robert M Graham, Nilesh J Samani, Nabila Bouatia-Naji, Mark K Bakker, Ynte M Ruigrok, David Adlam, Takiy-Eddine Berrandou, Adrien Georges, Christopher P Nelson, Eleni Giannoulatou, Joséphine Henry, Lijiang Ma, Montgomery Blencowe, Tamiel N Turley, Min-Lee Yang, Sandesh Chopade, Chris Finan, Peter S Braund, Ines Sadeg-Sayoud, Siiri E Iismaa, Matthew L Kosel, Xiang Zhou, Stephen E Hamby, Jenny Cheng, Lu Liu, Ingrid Tarr, David W M Muller, Valentina d'Escamard, Annette King, Liam R Brunham, Ania A Baranowska-Clarke, Stéphanie Debette, Philippe Amouyel, Jeffrey W Olin, Snehal Patil, Stephanie E Hesselson, Keerat Junday, Stavroula Kanoni, Krishna G Aragam, Adam S Butterworth, CARDIoGRAMPlusC4D, MEGASTROKE, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, Marysia S Tweet, Rajiv Gulati, Nicolas Combaret, DISCO register, Daniella Kadian-Dodov, Jonathan M Kalman, Diane Fatkin, Aroon D Hingorani, Jacqueline Saw, Tom R Webb, Sharonne N Hayes, Xia Yang, Santhi K Ganesh, Timothy M Olson, Jason C Kovacic, Robert M Graham, Nilesh J Samani, Nabila Bouatia-Naji, Mark K Bakker, Ynte M Ruigrok
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 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.
Conflict of interest statement
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.
© 2023. The Author(s).
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