Tamiel N Turley1, Megan M O'Byrne2, Matthew L Kosel2, Mariza de Andrade2, Rajiv Gulati3, Sharonne N Hayes3, Marysia S Tweet3, Timothy M Olson3,4. 1. Molecular Pharmacology and Experimental Therapeutics Track, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota. 2. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. 3. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota. 4. Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.
Abstract
Importance: Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death. Objective: To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility. Design, Setting, and Participants: This single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD registry from August 30, 2011, to August 2, 2018. Data analysis was performed from June 21, 2017, to December 30, 2019. Main Outcomes and Measures: Genetic loci and positional candidate genes associated with SCAD. Results: This study included 484 white women with SCAD (mean [SD] age, 46.6 [9.2] years) and 1477 white female controls in the discovery cohort (mean [SD] age, 64.0 [14.5] years) and 183 white women with SCAD (mean [SD] age, 47.1 [9.9] years) and 340 white female controls in the replication cohort (mean [SD] age, 51.0 [15.3] years). Associations with SCAD risk reached genome-wide significance at 3 loci (1q21.3 [OR, 1.78; 95% CI, 1.51-2.09; P = 2.63 × 10-12], 6p24.1 [OR, 1.77; 95% CI, 1.51-2.09; P = 7.09 × 10-12], and 12q13.3 [OR, 1.67; 95% CI, 1.42-1.97; P = 3.62 × 10-10]), and 7 loci had evidence suggestive of an association (1q24.2 [OR, 2.10; 95% CI, 1.58-2.79; P = 2.88 × 10-7], 3q22.3 [OR, 1.47; 95% CI, 1.26-1.71; P = 6.65 × 10-7], 4q34.3 [OR, 1.84; 95% CI, 1.44-2.35; P = 9.80 × 10-7], 8q24.3 [OR, 2.57; 95% CI, 1.76-3.75; P = 9.65 × 10-7], 15q21.1 [OR, 1.75; 95% CI, 1.40-2.18; P = 7.23 × 10-7], 16q24.1 [OR, 1.91; 95% CI, 1.49-2.44; P = 2.56 × 10-7], and 21q22.11 [OR, 2.11; 95% CI, 1.59-2.82; P = 3.12 × 10-7]) after adjusting for the top 5 principal components. Associations were validated for 5 of the 10 risk alleles in the replication cohort. In a meta-analysis of the discovery and replication cohorts, associations for the 5 SNVs were significant, with relatively large effect sizes (1q21.3 [OR, 1.77; 95% CI, 1.54-2.03; P = 3.26 × 10-16], 6p24.1 [OR, 1.71; 95% CI, 1.49-1.97; P = 4.59 × 10-14], 12q13.3 [OR, 1.69; 95% CI, 1.47-1.94; P = 1.42 × 10-13], 15q21.1 [OR, 1.79; 95% CI, 1.48-2.17; P = 2.12 × 10-9], and 21q22.11 [OR, 2.18; 95% CI, 1.70-2.81; P = 1.09 × 10-9]). Each index SNV was within or near a gene highly expressed in arterial tissue and previously linked to SCAD (PHACTR1) and/or other vascular disorders (LRP1, LINC00310, and FBN1). Conclusions and Relevance: This study revealed 5 replicated risk loci and positional candidate genes for SCAD, most of which are associated with extracoronary arteriopathies. Moreover, the alternate alleles of 3 SNVs have been previously associated with atherosclerotic coronary artery disease, further implicating allelic susceptibility to coronary artery atherosclerosis vs dissection.
Importance: Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death. Objective: To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility. Design, Setting, and Participants: This single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD registry from August 30, 2011, to August 2, 2018. Data analysis was performed from June 21, 2017, to December 30, 2019. Main Outcomes and Measures: Genetic loci and positional candidate genes associated with SCAD. Results: This study included 484 white women with SCAD (mean [SD] age, 46.6 [9.2] years) and 1477 white female controls in the discovery cohort (mean [SD] age, 64.0 [14.5] years) and 183 white women with SCAD (mean [SD] age, 47.1 [9.9] years) and 340 white female controls in the replication cohort (mean [SD] age, 51.0 [15.3] years). Associations with SCAD risk reached genome-wide significance at 3 loci (1q21.3 [OR, 1.78; 95% CI, 1.51-2.09; P = 2.63 × 10-12], 6p24.1 [OR, 1.77; 95% CI, 1.51-2.09; P = 7.09 × 10-12], and 12q13.3 [OR, 1.67; 95% CI, 1.42-1.97; P = 3.62 × 10-10]), and 7 loci had evidence suggestive of an association (1q24.2 [OR, 2.10; 95% CI, 1.58-2.79; P = 2.88 × 10-7], 3q22.3 [OR, 1.47; 95% CI, 1.26-1.71; P = 6.65 × 10-7], 4q34.3 [OR, 1.84; 95% CI, 1.44-2.35; P = 9.80 × 10-7], 8q24.3 [OR, 2.57; 95% CI, 1.76-3.75; P = 9.65 × 10-7], 15q21.1 [OR, 1.75; 95% CI, 1.40-2.18; P = 7.23 × 10-7], 16q24.1 [OR, 1.91; 95% CI, 1.49-2.44; P = 2.56 × 10-7], and 21q22.11 [OR, 2.11; 95% CI, 1.59-2.82; P = 3.12 × 10-7]) after adjusting for the top 5 principal components. Associations were validated for 5 of the 10 risk alleles in the replication cohort. In a meta-analysis of the discovery and replication cohorts, associations for the 5 SNVs were significant, with relatively large effect sizes (1q21.3 [OR, 1.77; 95% CI, 1.54-2.03; P = 3.26 × 10-16], 6p24.1 [OR, 1.71; 95% CI, 1.49-1.97; P = 4.59 × 10-14], 12q13.3 [OR, 1.69; 95% CI, 1.47-1.94; P = 1.42 × 10-13], 15q21.1 [OR, 1.79; 95% CI, 1.48-2.17; P = 2.12 × 10-9], and 21q22.11 [OR, 2.18; 95% CI, 1.70-2.81; P = 1.09 × 10-9]). Each index SNV was within or near a gene highly expressed in arterial tissue and previously linked to SCAD (PHACTR1) and/or other vascular disorders (LRP1, LINC00310, and FBN1). Conclusions and Relevance: This study revealed 5 replicated risk loci and positional candidate genes for SCAD, most of which are associated with extracoronary arteriopathies. Moreover, the alternate alleles of 3 SNVs have been previously associated with atherosclerotic coronary artery disease, further implicating allelic susceptibility to coronary artery atherosclerosis vs dissection.
Authors: Ingrid Tarr; Stephanie Hesselson; Siiri E Iismaa; Emma Rath; Steven Monger; Michael Troup; Ketan Mishra; Claire M Y Wong; Pei-Chen Hsu; Keerat Junday; David T Humphreys; David Adlam; Tom R Webb; Anna A Baranowska-Clarke; Stephen E Hamby; Keren J Carss; Nilesh J Samani; Monique Bax; Lucy McGrath-Cadell; Jason C Kovacic; Sally L Dunwoodie; Diane Fatkin; David W M Muller; Robert M Graham; Eleni Giannoulatou Journal: Circ Genom Precis Med Date: 2022-05-18
Authors: Rainer Malik; Nathalie Beaufort; Simon Frerich; Benno Gesierich; Marios K Georgakis; Kristiina Rannikmäe; Amy C Ferguson; Christof Haffner; Matthew Traylor; Michael Ehrmann; Cathie L M Sudlow; Martin Dichgans Journal: Brain Date: 2021-10-22 Impact factor: 15.255
Authors: Vanessa L Kronzer; Alex D Tarabochia; Angie S Lobo Romero; Nicholas Y Tan; Thomas J O'Byrne; Cynthia S Crowson; Tamiel N Turley; Elena Myasoedova; John M Davis; Claire E Raphael; Rajiv Gulati; Sharonne N Hayes; Marysia S Tweet Journal: J Am Coll Cardiol Date: 2020-11-10 Impact factor: 24.094
Authors: Tamiel N Turley; Matthew L Kosel; William R Bamlet; Rajiv Gulati; Sharonne N Hayes; Marysia S Tweet; Timothy M Olson Journal: Circ Genom Precis Med Date: 2021-08-13
Authors: Jacqueline Saw; Min-Lee Yang; Mark Trinder; Catherine Tcheandjieu; Chang Xu; Andrew Starovoytov; Isabelle Birt; Michael R Mathis; Kristina L Hunker; Ellen M Schmidt; Linda Jackson; Natalia Fendrikova-Mahlay; Matthew Zawistowski; Chad M Brummett; Sebastian Zoellner; Alexander Katz; Dawn M Coleman; Kirby Swan; Christopher J O'Donnell; Xiang Zhou; Jun Z Li; Heather L Gornik; Themistocles L Assimes; James C Stanley; Liam R Brunham; Santhi K Ganesh Journal: Nat Commun Date: 2020-09-04 Impact factor: 14.919
Authors: Adrien Georges; Min-Lee Yang; Takiy-Eddine Berrandou; Mark K Bakker; Ozan Dikilitas; Soto Romuald Kiando; Lijiang Ma; Benjamin A Satterfield; Sebanti Sengupta; Mengyao Yu; Jean-François Deleuze; Delia Dupré; Kristina L Hunker; Sergiy Kyryachenko; Lu Liu; Ines Sayoud-Sadeg; Laurence Amar; Chad M Brummett; Dawn M Coleman; Valentina d'Escamard; Peter de Leeuw; Natalia Fendrikova-Mahlay; Daniella Kadian-Dodov; Jun Z Li; Aurélien Lorthioir; Marco Pappaccogli; Aleksander Prejbisz; Witold Smigielski; James C Stanley; Matthew Zawistowski; Xiang Zhou; Sebastian Zöllner; Philippe Amouyel; Marc L De Buyzere; Stéphanie Debette; Piotr Dobrowolski; Wojciech Drygas; Heather L Gornik; Jeffrey W Olin; Jerzy Piwonski; Ernst R Rietzschel; Ynte M Ruigrok; Miikka Vikkula; Ewa Warchol Celinska; Andrzej Januszewicz; Iftikhar J Kullo; Michel Azizi; Xavier Jeunemaitre; Alexandre Persu; Jason C Kovacic; Santhi K Ganesh; Nabila Bouatia-Naji Journal: Nat Commun Date: 2021-10-15 Impact factor: 17.694