Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.
Eur Heart J
; 42(9): 919-933, 2021 03 01.
Article
em En
| MEDLINE
| ID: mdl-33532862
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 ANDRESULTS:
We carried out a genome-wide association study for MI in the UK Biobank (nâ¼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (nâ¼167 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 (nâ¼165 000) and 16 independent angiography-based cohorts (nâ¼27 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-1ß (vs. vehicle), and associated with smooth muscle cell migration in vitro.CONCLUSIONS:
A large-scale analysis comprising â¼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Doença da Artéria Coronariana
/
Infarto do Miocárdio
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article