Jaana A Hartiala1, Yi Han1,2, Qiong Jia1,2, James R Hilser1,2, Pin Huang1,2, Janet Gukasyan1,2, William S Schwartzman1,2, Zhiheng Cai1,2, Subarna Biswas1, David-Alexandre Trégouët3, Nicholas L Smith4,5,6, Marcus Seldin7, Calvin Pan8, Margarete Mehrabian9, Aldons J Lusis8,9,10, Peter Bazeley11,12,13, Yan V Sun14,15, Chang Liu14,16, Arshed A Quyyumi16, Markus Scholz17,18, Joachim Thiery18,19, Graciela E Delgado20, Marcus E Kleber20, Winfried März20,21,22, Laurence J Howe23, Folkert W Asselbergs23,24,25, Marion van Vugt25, Georgios J Vlachojannis25, Riyaz S Patel23,26, Leo-Pekka Lyytikäinen27,28,29, Mika Kähönen30,31, Terho Lehtimäki27,28, Tuomo V M Nieminen32, Pekka Kuukasjärvi33, Jari O Laurikka33,34, Xuling Chang35,36, Chew-Kiat Heng35,36, Rong Jiang37, William E Kraus38,39, Elizabeth R Hauser38,40, Jane F Ferguson41, Muredach P Reilly42,43, Kaoru Ito44, Satoshi Koyama44, Yoichiro Kamatani45,46,47, Issei Komuro48, Lindsey K Stolze49, Casey E Romanoski49, Mohammad Daud Khan50,51,52,53, Adam W Turner50,51,52,53, Clint L Miller50,51,52,53, Redouane Aherrahrou50,51, Mete Civelek50,51, Lijiang Ma54, Johan L M Björkegren54,55, S Ram Kumar56, W H Wilson Tang11,12,13, Stanley L Hazen12,13, Hooman Allayee1,2. 1. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2250 Alcazar Street, CSC202, Los Angeles, CA 90033, USA. 2. Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. 3. Institut National pour la Santé et la Recherche Médicale (INSERM) UMR_S 1219, Bordeaux Population Health Research Center, University of Bordeaux, 33076 Bordeaux, France. 4. Department of Epidemiology, University of Washington, Seattle, WA 98101, USA. 5. Department of Veterans Affairs, Seattle Epidemiologic Research and Information Center, Office of Research and Development, Seattle, WA 98108, USA. 6. Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA 98101, USA. 7. Department of Biological Chemistry and Center for Epigenetics and Metabolism, UC Irvine School of Medicine, Irvine, CA 92697, USA. 8. Department of Human Genetics, David Geffen School of Medicine of UCLA, Los Angeles, CA 90095, USA. 9. Department of Medicine, David Geffen School of Medicine of UCLA, Los Angeles, CA 90095, USA. 10. Department of Microbiology, Immunology, & Molecular Genetics, David Geffen School of Medicine of UCLA, Los Angeles, CA 90095, USA. 11. Center for Clinical Genomics, Cleveland Clinic, Cleveland, OH 44195, USA. 12. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. 13. Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195, USA. 14. Department of Epidemiology, Emory University Rollins School of Public Health, 1518 Clifton Rd. NE, Atlanta, GA 30322, USA. 15. Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA 30322, USA. 16. Division of Cardiology, Department of Medicine, Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine, 1462 Clifton Rd NE, Suite # 507, Atlanta, GA 30322, USA. 17. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, Germany. 18. LIFE Research Center for Civilization Diseases, University of Leipzig, 04103 Leipzig, Germany. 19. Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital, 04103 Leipzig, Germany. 20. Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. 21. SYNLAB Academy, SYNLAB Holding Deutschland GmbH, 86156 Augsburg, Germany. 22. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria. 23. Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London WC1E 6HX, UK. 24. Health Data Research UK and Institute of Health Informatics, University College London, London NW1 2DA, UK. 25. Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands. 26. Bart's Heart Centre, St Bartholomew's Hospital, London EC1A 2DA, UK. 27. Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland. 28. Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33014, Finland. 29. Department of Cardiology, Heart Center, Tampere University Hospital, Tampere 33521, Finland. 30. Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland. 31. Department of Clinical Physiology, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33014, Finland. 32. Department of Internal Medicine, Päijät-Häme Central Hospital, Lahti 15850, Finland. 33. Department of Cardio-Thoracic Surgery, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33014, Finland. 34. Department of Cardio-Thoracic Surgery, Heart Center, Tampere University Hospital, Tampere 33521, Finland. 35. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore. 36. Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore 119074, Singapore. 37. Department of Psychiatry & Behavioral Sciences, Duke University School of Medicine Durham, NC 27710, USA. 38. Duke Molecular Physiology Institute, Duke University School of Medicine Durham, NC 27710, USA. 39. Department of Medicine, Duke University School of Medicine Durham, NC 27710, USA. 40. Department of Biostatistics & Bioinformatics, Duke University School of Medicine Durham, NC 27710, USA. 41. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. 42. Cardiometabolic Genomics Program, Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA. 43. Irving Institute for Clinical and Translational Research, Columbia University, New York, NY 10032, USA. 44. Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan. 45. Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa 230-0045, Japan. 46. Human Disease Genomics, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan. 47. Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-0071, Japan. 48. Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 49. Department of Cellular and Molecular Medicine, University of Arizona College of Medicine, Tucson, AZ 85721, USA. 50. Center for Public Health Genomics, University of Virginia, Charlottesville University of Virginia, Charlottesville, VA 22904, USA. 51. Department of Biomedical Engineering, University of Virginia, Charlottesville University of Virginia, Charlottesville, VA 22904, USA. 52. Department of Biochemistry & Molecular Genetics, University of Virginia, Charlottesville University of Virginia, Charlottesville, VA 22904, USA. 53. Department of Public Health Sciences, University of Virginia, Charlottesville University of Virginia, Charlottesville, VA 22904, USA. 54. Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. 55. Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, 141 57 Huddinge, Sweden. 56. Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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