Unfolding and disentangling coronary vascular disease through genome-wide association studies

Abstract

From the day we are born, our arteries deteriorate. As we age, molecular and cellular decay combined with a never-ceasing attack by internal and external factors (think: circulating metabolites, toxins from smoking, elevated blood pressure, unhealthy diet constituents, microbes) weaken the natural endothelial barrier lining of our arteries. Endothelial damage eventually gives way to the formation of a fatty streak combined with changes in the intima and media, leading to a thickening and hardening of the artery that may occur together with a gradual constrictive or expansive remodelling and arterial inflammation: commonly known as atherosclerosis. By the time we reach middle age, plaques have formed to varying degrees, some of which progress to an unstable form until a tipping point is reached and a myocardial infarction (MI) ensues. Atherosclerosis is highly heritable. Findings from large-scale genome-wide association studies (GWAS) and family studies seem to confer additive information: a substantial portion of our lifetime risk of cardiovascular disease (CVD) is explained by variations in our DNA sequence, while gene–gene and gene–environment interactions also contribute to our cardiovascular heritage. Over 160 genetic loci are associated with risk of coronary artery disease (CAD) and MI, together explaining 25% of the heritability. Cardiovascular genetics studies proxies of atherosclerotic disease progression (carotid intima-media thickness and coronary calcification), relevant traits, risk factors (circulating lipid levels, blood pressure, coagulation factors), and atherosclerotic plaque characteristics. However, for roughly half of the loci, the causal variant(s), gene(s), and mechanism(s) are unclear. Single-cell RNA sequencing confirms the cellular heterogeneity of atherosclerotic plaques, thereby complicating translation to causal gene networks and therapeutic targets. These subtle genetic effects act differently depending on the disease stage; at a population level, those having a high polygenic burden develop atherosclerosis sooner and are at higher risk. Thus, the processes involved in atherosclerosis and thereby the associated genetic risk loci can be unfolded to an atherosclerotic time scale (Figure 1). In this respect, Hartiala et al. followed the interesting hypothesis that to some degree genetic risk factors might differentially influence risk for atherosclerosis or MI, by affecting plaque stability or thrombotic events. Based on a meta-analysis of GWAS data for MI from the UK Biobank and CARDIoGRAMplusC4D consortium and subsequent replication studies, the authors firmly established eight novel genetic risk loci for MI, six of which showed stronger effect sizes for MI than for CAD. Moreover, a locus on chromosome 1p21.3, encompassing choline-like transporter 3 gene (SLC44A3), is significantly associated with MI in patients with CAD, but not with lifetime risk of coronary atherosclerosis itself. Post-GWAS analyses conducted by Hartiala et al., including association studies with known CAD risk factors, several biomarkers, and plasma levels of metabolites, did not reveal any mechanistic insights. However, by studying gene expression data, the authors showed that gene expression of SLC44A3 is increased in the aorta of risk-allele carriers. Furthermore, the risk-allele is associated with increased expression of SLC44A3 in ischaemic coronary arteries, and in human aortic