Genome-wide analysis identifies novel susceptibility loci for myocardial infarction
Authors: Hartiala Jaana A , Han Yi , Jia Qiong , Hilser James R , Huang Pin , Gukasyan Janet , Schwartzman William S , Cai Zhiheng , Biswas Subarna , Trégouët David-Alexandre , Smith Nicholas L ,   The INVENT Consortium,   The CHARGE Consortium Hemostasis Working Group,   The GENIUS-CHD Consortium, Seldin Marcus , Pan Calvin , Mehrabian Margarete , Lusis Aldons J , Bazeley Peter , Sun Yan V , Liu Chang , Quyyumi Arshed A , Scholz Markus , Thiery Joachim , Delgado Graciela E , Kleber Marcus E , März Winfried , Howe Laurence J , Asselbergs Folkert W , van Vugt Marion , Vlachojannis Georgios J , Patel Riyaz S , Lyytikäinen Leo-Pekka , Kähönen Mika , Lehtimäki Terho , Nieminen Tuomo V M , Kuukasjärvi Pekka , Laurikka Jari O , Chang Xuling , Heng Chew-Kiat , Jiang Rong , Kraus William E , Hauser Elizabeth R , Ferguson Jane F , Reilly Muredach P , Ito Kaoru , Koyama Satoshi , Kamatani Yoichiro , Komuro Issei ,   Biobank Japan, Stolze Lindsey K , Romanoski Casey E , Khan Mohammad Daud , Turner Adam W , Miller Clint L , Aherrahrou Redouane , Civelek Mete , Ma Lijiang , Björkegren Johan L M , Kumar S Ram , Tang W H Wilson , Hazen Stanley L , Allayee Hooman 
Published: December 2020

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.