Genetics of coronary artery disease: discovery, biology and clinical translation

Abstract

Coronary artery disease is the leading global cause of mortality. Long recognized to be heritable, recent advances have started to unravel the genetic architecture of the disease. Common variant association studies have linked approximately 60 genetic loci to coronary risk. Large-scale gene sequencing efforts and functional studies have facilitated a better understanding of causal risk factors, elucidated underlying biology and informed the development of new therapeutics. Moving forwards, genetic testing could enable precision medicine approaches by identifying subgroups of patients at increased risk of coronary artery disease or those with a specific driving pathophysiology in whom a therapeutic or preventive approach would be most useful.

Figure 1. Physiologic pathways related to genetic loci associated with coronary artery disease

Genetic loci identified to date are displayed along with presumed relation to causal pathway. Loci are labelled based on nearest genes because the causal genes and variants have not been definitively identified for most loci; this commonly used form of annotation may prove incorrect in some cases. Adapted from REF. .

Figure 2. Human genetics to facilitate drug development – Lipoprotein

(a). Human genetics data serves as the foundation for ongoing efforts to develop therapies to reduce lipoprotein(a) levels, a causal risk factor for coronary artery disease. a | The selection of lipoprotein(a) as a therapeutic target was supported by a 2009 genome-wide association study comparing 1,145 CAD cases to 3,352 controls, noting a robust association between variants near the LPA gene, levels of circulating lipoprotein(a), and risk of coronary artery disease. b | A dose-response relationship was noted, such that a given variant’s impact on circulating lipoprotein(a) levels was predictive of the association with CAD (Reproduced with permission from REF 91) c | In order to anticipate the full spectrum of phenotypic consequences of lipoprotein(a) reduction, a phenome-wide association study was performed among participants of the UK Biobank. A genetically-mediated one standard deviation decrease in levels of lipoprotein(a) was associated with a reduced risk of six distinct diseases (Reproduced with permission from REF 91). d | An antisense oligonucleotide targeting hepatic production of lipoprotein(a) was associated with a >80% decrease in circulating levels, providing proof-of-principle that targeting this causal pathway in a highly specific fashion (Reproduced with permission from REF 83).

Figure 3. Mendelian randomization to identify causal biomarkers for risk of coronary artery disease

a | Mendelian randomization analyses require that: 1) a genetic variant (or group of variants) is robustly associated with the biomarker of interest; and 2) the genetic variant is independent of confounders that influence the biomarker or risk of CAD; and 3) any impact of the genetic variant on risk of CAD is mediated by the biomarker (as opposed to other pleiotropic genetic effects). Because genetic variants are assorted within the population at time of conception largely at random, these analyses are less susceptible to the issues of confounding or reverse causality that commonly limit causal inference from observational epidemiology. An important limitation of this study is that it requires a robust relationship between the genetic variant and a biomarker – a small effect size mandates a large number of individuals afflicted with CAD to achieve adequate power. b | For example, rs6511720 is an intronic variant in the LDL receptor (LDLR) gene. Each copy of the ‘T’ allele is associated with a lower LDL cholesterol and an decreased risk of CAD. Among biomarkers linked with coronary artery disease in the population, studies performed to date have supported a causal relationship for some (e.g. LDL cholesterol, triglyceride-rich lipoproteins, lipoprotein(a)) and a non-causal relationship for others (e.g., HDL cholesterol, C-Reactive Protein).

Figure 4. Precision medicine guided by human genetics

Genetic testing of 1,000 people would identify 1–2% of individuals with a monogenic driver of risk. For example, individuals with familial hypercholesterolemia may derive particular benefit from lowering of LDL cholesterol levels with PCSK9 inhibitors. Second, damaging mutations in LPL or APOA5 increase CAD risk by preventing the clearance of dietary fat and triglyceride-rich lipoproteins from the bloodstream – this risk might be directly attenuated through use of inhibition of APOC3. Thirdly, those with a genetic predisposition to increased lipoprotein(a), i.e. at least two risk variants (at SNP sites rs10455872 or rs3798220) as previously characterized, might be offered an antisense oligonucleotide to decrease circulating levels. Importantly, any such therapies would likely be incorporated in addition to guideline-based cardiovascular risk reduction therapeutics. Furthermore, confirmation that targeted PCSK9 inhibition, APOC3 inhibition, or Lp(a) reduction leads to reduction in CAD events in clinical trials is needed prior to widespread implementation. By contrast, 20% of individuals tested would be in the top quintile of a polygenic risk score – this population might be targeted for aggressive lifestyle or pharmacologic therapies beyond current treatment guidelines.

Figure 5

Lipoprotein lipase (LPL) is an enzyme anchored to the endothelial cells lining blood capillaries. Dietary fat is absorbed by the small intestine and enters the blood stream as triglyceride-rich lipoprotein particles known as chylomicrons. These chylomicrons are hydrolysed by LPL to provide free fatty acids (used for energy by muscle tissue or deposited into fat stores) and chylomicron remnant particles. LPL plays an additional role in hydrolysing very-low density lipoprotein (VLDL) particles secreted by the liver to produce intermediate density lipoprotein (IDL), subsequently degraded into low-density lipoprotein (LDL) particles by hepatic lipase (HL). Both chylomicron remnants and LDL can penetrate the vessel wall and propagate atherosclerotic plaque. LPL activity is the rate-determining step in clearance of dietary fat from the circulation and is highly regulated in the body – apolipoprotein A-V and apolipoprotein C-II activate LPL and apolipoprotein C-III (APOC-III), Angiopoietin-like 4, and angiopoietin-like 3 (ANGPTL3) each inhibit LPL activity. Rare variant association studies have supported a link between several of the proteins involved in the LPL pathway and CAD, including LPL itself, apoC-III, apoA-V, and ANGPTL4 (Table 1).