TY - JOUR
T1 - Genome-wide analysis identifies novel susceptibility loci for myocardial infarction
AU - INVENT 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 - Lyytikäinen, Leo-Pekka
AU - Kähönen, Mika
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 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.
PY - 2021/3/1
Y1 - 2021/3/1
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 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.
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 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.
KW - Coronary Artery Disease/genetics
KW - Endothelial Cells
KW - Genetic Predisposition to Disease/genetics
KW - Genome-Wide Association Study
KW - Humans
KW - Japan
KW - Myocardial Infarction/genetics
KW - Polymorphism, Single Nucleotide/genetics
KW - Risk Factors
U2 - https://doi.org/10.1093/eurheartj/ehaa1040
DO - https://doi.org/10.1093/eurheartj/ehaa1040
M3 - Article
C2 - 33532862
SN - 0195-668X
VL - 42
SP - 919
EP - 933
JO - European Heart journal
JF - European Heart journal
IS - 9
ER -