Genome-wide analysis identifies novel susceptibility loci for myocardial infarction

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, INVENT Consortium, CHARGE Consortium Hemostasis Working Group, GENIUS-CHD Consortium, Marcus Seldin, Calvin Pan, Margarete Mehrabian, Aldons J. Lusis, Peter Bazeley, Yan V. SunChang 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

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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.

Original languageEnglish
Pages (from-to)919-933
Number of pages15
JournalEuropean Heart Journal
Volume42
Issue number9
DOIs
Publication statusPublished - 2021
Publication typeA1 Journal article-refereed

Keywords

  • Genetic factors
  • Genome-wide association study
  • Meta-analysis
  • Myocardial infarction
  • SLC44A3

Publication forum classification

  • Publication forum level 3

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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