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-1 (vs. vehicle), and associated with smooth muscle cell migration in vitro.
A large-scale analysis comprising ~831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.
Sex-specific Genetic Determinants of Cardiometabolic Traits
Although cardiovascular disease (CVD) has traditionally been viewed as a disease of men, new evidence suggests the existence of distinct differences in the risk factors, development, and outcomes between the two sexes. For example, our recent studies have revealed that the genetic factors for several intermediate cardiometabolic traits, such as blood levels of certain amino acids (i.e. glycine) and lipids (i.e. ceramides), represent potentially novel sex-specific mechanisms for CVD. This project proposes to build on our observations using genetic and clinical cardiometabolic data from the UK Biobank. By helping to determine the genetic basis of CVD, our proposed analyses could identify novel therapeutic targets and/or risk stratification tools. Thus, these studies would be consistent with UK Biobank's stated purpose to improve the prevention, diagnosis and treatment of a wide range of illnesses, including heart diseases. The genotype and specific clinical data we request from all UK Biobank participants will be used for statistical analyses. These large-scale computations will specifically test for genetic associations in men and women separately. We will also carry out these sex-stratified tests with the genetic risk factors all combined together in what is typically referred to as `genetic risk score analysis.` Full cohort for genotypes and clinical binary and quantitative CVD traits.
|Lead investigator:||Hooman Allayee|
|Lead institution:||University of Southern California|