Year: 2020
Type: article
Study design: Observational Study
Abstract: AIMS: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. METHODS AND RESULTS: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro. CONCLUSIONS: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.
Source: European Heart Journal
Authors: Jaana A Hartiala, Yi Han, Qiong Jia, James R Hilser, Pin Huang, Janet Gukasyan, William S Schwartzman, Zhiheng Cai, Subarna Biswas, David-Alexandre Trégouët, Nicholas L Smith, Marcus Seldin, Calvin Pan, Margarete Mehrabian, Aldons J Lusis, Peter Bazeley, Yan V Sun, Chang Liu, Arshed A Quyyumi, Markus Scholz, Joachim Thiery, Graciela E Delgado, Marcus E Kleber, Winfried März, Laurence J Howe, Folkert W Asselbergs, Marion van Vugt, Georgios J Vlachojannis, Riyaz S Patel, Leo-Pekka Lyytikäinen, Mika Kähönen, Terho Lehtimäki, Tuomo V M Nieminen, Pekka Kuukasjärvi, Jari O Laurikka, Xuling Chang, Chew-Kiat Heng, Rong Jiang, William E Kraus, Elizabeth R Hauser, Jane F Ferguson, Muredach P Reilly, Kaoru Ito, Satoshi Koyama, Yoichiro Kamatani, Issei Komuro, Biobank Japan, Lindsey K Stolze, Casey E Romanoski, Mohammad Daud Khan, Adam W Turner, Clint L Miller, Redouane Aherrahrou, Mete Civelek, Lijiang Ma, Johan L M Björkegren, S Ram Kumar, W H Wilson Tang, Stanley L Hazen, Hooman Allayee
Institutions: University of Southern California, Université de Bordeaux, Inserm, Bordeaux Population Health, United States Department of Veterans Affairs, Kaiser Permanente Washington Health Research Institute, University of Washington, VA Office of Research and Development, Seattle Epidemiologic Information and Research Center, University of California, Irvine, University of California, Los Angeles, Cleveland Clinic, Emory University, Leipzig University, University Hospital Leipzig, Heidelberg University, Medizinische Fakultät Mannheim, Medical University of Graz, Synlab (Germany), University College London, Utrecht University, University Medical Center Utrecht, Health Data Research UK, St Bartholomew's Hospital, Tampere University, Tampere University Hospital, Fimlab (Finland), University of Tampere, Päijät-Hämeen Keskussairaala, National University of Singapore, National University Health System, Duke University, Duke Medical Center, Vanderbilt University Medical Center, Columbia University Irving Medical Center, Columbia University, RIKEN Center for Integrative Medical Sciences, Kyoto University, Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, The University of Tokyo, University of Arizona, University of Virginia, Icahn School of Medicine at Mount Sinai, Karolinska University Hospital, Karolinska Institutet, Integrated Cardio Metabolic Centre
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: American Heart Association, Foundation for Cardiovascular Research, Indiana Corn Marketing Council, National Institute for Health and Care Research, British Heart Foundation, University College London, European Commission, Agence Nationale de la Recherche, Fondation Leducq, Suomen Kulttuurirahasto, Karolinska Institutet, Vetenskapsrådet, Emil Aaltosen Säätiö, Sydäntutkimussäätiö, Université de Bordeaux, Tampereen Tuberkuloosisäätiö, Tays, National Institutes of Health, Japan Society for the Promotion of Science, Horizon 2020, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, National Institute on Minority Health and Health Disparities
Awards: Understanding coronary artery disease genes, G1057444701, G1094295515, Systems genetics approach to inflammatory mechanisms in atherosclerosis, G1408218111, G1763104746, Genetic and Environmental Determinants of Asthma Endophenotypes, G198835066, G2208554754, G2247587933, G2330237237, G234837756, A high-dimensional approach for unwinding immune-metabolic causes of cardiovascular disease-depression multimorbidities, G3007000982, G3093785025, G3213590351, A novel mechanism by which the CAD risk gene MIA3 regulates phenotypic transition of vascular smooth muscle cells, G33539551, Elucidation of genetic factors that define myocardial vulnerability as a basis for the development of heart failure, Nutrigenetic Intervention to Reduce Liver Fat in Hispanics - Supplement, Defining the Roles of Smooth Muscle Cells and Other Extracellular Matrix Producing Cells in Late Stage Atherosclerotic Plaque Pathogenesis, G4233991685, Genetic Regulation of Vascular Smooth Muscle Gene Expression, G4554046426, Gut microbiota and metabolite interactions in atherosclerosis, HDL Structure, Function and Dysfunction, G5512925732, Oxidation in Inflammation and Cardiovascular Disease, G5569704551, Initiative d’excellence de l’Université de Bordeaux, G6201718267, G6520767105, Genetic and phenotypic risk factors for subsequent coronary heart disease events, INTEGRATIVE GENETIC APPROACHES TO GENE-AIR POLLUTION INTERACTIONS IN ASTHMA, G6711500785, G692875121, G695633315, G712881263, G7768179268, G8046657168, Integrated systems genetics applied to high-dimensional data from multiple tissues, the microbiome and portal vein to identify new diagnostic and therapy targets for cardiometabolic diseases in obese, A strategy for discovery of endocrine interactions, G865790386, G87592374, G8863740854, G9000001775, G9000007664, G9000008751, G9000011841, G9000016276, G9000023732, G9000078917, G9000091549, G9000119601, G9000149409, G9000216519, G9000221634, G9000224307, G9000229334, G9000252138, G9000269349, Systems Genetics Dissection of Non-alcoholic Steatohepatitis, Multimodal genetic regulatory architecture of coronary artery disease, Southwest Environmental Health Sciences Center
OpenAlex ID: W3126364712