TY - JOUR
T1 - Genome-wide analysis identifies novel susceptibility loci for myocardial infarction
AU - The INVENT Consortium
AU - The CHARGE Consortium Hemostasis Working Group
AU - The GENIUS-CHD Consortium
AU - Hartiala, Jaana A.
AU - Han, Yi
AU - Jia, Qiong
AU - Hilser, James R.
AU - Huang, Pin
AU - Gukasyan, Janet
AU - Schwartzman, William S.
AU - Cai, Zhiheng
AU - Biswas, Subarna
AU - Trégouët, David Alexandre
AU - Smith, Nicholas L.
AU - Seldin, Marcus
AU - Pan, Calvin
AU - Mehrabian, Margarete
AU - Lusis, Aldons J.
AU - Bazeley, Peter
AU - Sun, Yan V.
AU - Liu, Chang
AU - Quyyumi, Arshed A.
AU - Scholz, Markus
AU - Thiery, Joachim
AU - Delgado, Graciela E.
AU - Kleber, Marcus E.
AU - März, Winfried
AU - Howe, Laurence J.
AU - Asselbergs, Folkert W.
AU - van Vugt, Marion
AU - Vlachojannis, Georgios J.
AU - Patel, Riyaz S.
AU - Kähönen, Mika
AU - Lyytikäinen, Leo Pekka
AU - Lehtimäki, Terho
AU - Nieminen, Tuomo V.M.
AU - Kuukasjärvi, Pekka
AU - Laurikka, Jari O.
AU - Chang, Xuling
AU - Heng, Chew Kiat
AU - Jiang, Rong
AU - Kraus, William E.
AU - Hauser, Elizabeth R.
AU - Ferguson, Jane F.
AU - Reilly, Muredach P.
AU - Ito, Kaoru
AU - Koyama, Satoshi
AU - Kamatani, Yoichiro
AU - Komuro, Issei
AU - Stolze, Lindsey K.
AU - Romanoski, Casey E.
AU - Khan, Mohammad Daud
AU - Turner, Adam W.
N1 - Publisher Copyright:
© The Author(s) 2021.
PY - 2021
Y1 - 2021
N2 - 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 We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta- and results 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-1b (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.
AB - 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 We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta- and results 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-1b (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.
KW - Genetic factors
KW - Genome-wide association study
KW - Meta-analysis
KW - Myocardial infarction
KW - SLC44A3
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U2 - 10.1093/eurheartj/ehaa1040
DO - 10.1093/eurheartj/ehaa1040
M3 - Article
C2 - 33532862
AN - SCOPUS:85102657935
SN - 0195-668X
VL - 42
SP - 919
EP - 933
JO - European Heart Journal
JF - European Heart Journal
IS - 9
ER -