Genetics of Coronary Atherosclerosis

Introduction

This chapter reviews current understanding of the genetic architecture of coronary atherosclerosis as gleaned from Mendelian and common, complex forms of the disease. Newly identified pathways and biologic mechanisms are highlighted before discussing the present and future role of genetic testing for the diagnosis, prognosis, and treatment of patients with coronary artery disease (CAD).

Heritability of Coronary Artery Disease

Familial clustering of CAD has long been observed and suggests an inherited basis for CAD and its downstream complication of myocardial infarction (MI). In the offspring cohort of the Framingham Heart Study, a parental history of premature CAD conferred a two- to three-fold increase in the age-specific incidence of cardiovascular events after adjustment for conventional CAD risk factors—implying a genetic basis for the observed susceptibility to CAD. Twin and family studies have estimated that the heritability of CAD is approximately 40% to 60%. Heritable effects appear most pronounced for early-onset CAD, denoting the importance of inherited over acquired risk factors for the development of premature disease. Furthermore, several risk factors for CAD, including plasma lipid concentrations, blood pressure, and type II diabetes mellitus, are themselves heritable and as such contribute to the overall heritability of the CAD/MI phenotype.

Varying patterns of inheritance have provided insights into the genetic underpinnings of CAD. Some forms of CAD demonstrate a simple, Mendelian inheritance pattern, manifest at a young age without the influence of environmental risk factors, and are typified by a single causal gene with a large effect size. Candidate gene studies and linkage analyses have elucidated these monogenic disorders through the study of patients and families with extreme phenotypes to identify causal genes contributing to the disease of interest.

However, the majority of CAD in the population exhibits a more complex and multifactorial inheritance pattern inconsistent with the ratios of Mendel. Such polygenic forms of CAD involve the interplay of many common DNA variants of small to moderate effect sizes, together with nongenetic factors, including both lifestyle and environment. Advancements in high-throughput DNA microarray technologies have permitted the identification of nearly 60 common DNA variants associated with CAD/MI through large-scale genetic association studies, accounting for approximately 13% of the cumulative genetic variance of CAD. Next-generation sequencing technologies and additional studies interrogating potential gene-environment interactions have begun to bridge the gap on the missing heritability of CAD and its risk factors.

Mendelian Causes of Coronary Artery Disease

Examples of Mendelian forms of CAD largely involve gene defects that lead to extremely high plasma concentrations of low-density lipoprotein cholesterol (LDL-C). One such disease is familial hypercholesterolemia (FH) where defects in the LDL receptor mediate disordered uptake of cellular LDL particles from the bloodstream ( Table 3.1 ). Investigations of homozygous FH patients led to the sequencing and identification of mutations in the LDL receptor ( LDLR ) gene, resulting in defective cellular uptake of LDL-C. LDLR mutations are associated with elevated plasma concentrations of LDL-C, typical physical stigmata of severe hypercholesterolemia—ie, tendon xanthomas and corneal arcus (see Fig. 7.4, Fig. 7.5 )—and premature coronary atherosclerosis. FH is inherited in a codominant pattern where the number of abnormal allelic copies (1 or 2) correlates directly with the severity of the FH phenotype.

Subsequent studies in FH patients without LDLR mutations led to the discovery of additional causal mutations in the APOB and PCSK9 genes, which encode for apolipoprotein B (ApoB) and proprotein convertase subtilisin/kexin type 9 (PCSK9), respectively. ApoB is a key protein on the LDL particle that facilitates its binding to the LDL receptor for cellular uptake and degradation. APOB mutations associating with FH were found to interrupt the binding of the ApoB protein to LDL receptor on the cell surface, leading to reduced LDL uptake and higher plasma LDL concentrations.

PCSK9 is highly expressed in the liver and regulates cholesterol homeostasis by binding to the LDL receptor and inducing its degradation. Gain-of-function mutations in the PCSK9 gene are associated with FH presumably due to reduced LDL receptor availability and a resultant decrease in LDL particle uptake. Similar to LDLR and APOB , mutations in PCSK9 demonstrate an autosomal dominant inheritance pattern, with one copy of the mutant allele leading to an FH phenotype. Notably, loss-of-function mutations in PCSK9 are associated with upregulation of LDL receptors, a marked reduction in LDL-C concentrations, and an 88% reduction in CAD risk.

Other Mendelian disorders of hypercholesterolemia mediate CAD but through an autosomal recessive pattern of inheritance. Two aberrant copies of the LDLRAP1 gene are causative for autosomal recessive hypercholesterolemia (ARH), the mechanism of which remains uncertain but appears to involve a defect in an adapter protein that disrupts the interaction between the LDL receptor and clathrin-coated pits. Individuals with ARH manifest an intermediate form of hypercholesterolemia somewhere between that of LDLR heterozygotes and LDLR homozygotes. Sitosterolemia is a rare autosomal recessive disorder of plant sterol metabolism caused by a defect in the genes encoding ATP-binding cassette (ABC) transporter proteins involved in the excretion of dietary plant sterols. The disease shares several clinical features with FH, such as tendon xanthomas and premature development of CAD. However, unlike FH, the disease is characterized by elevated plant sterol levels, whereas total cholesterol levels may be normal.

Attempts to uncover Mendelian forms of CAD/MI independent of the aforementioned lipoprotein pathways have been unsuccessful. A 21-kb deletion within the MEF2A gene (which encodes the myocyte enhancer factor [MEF] 2A transcription factor strongly expressed in the coronary endothelium) was initially identified as a putative autosomal dominant form of CAD/MI in a 21-member family with 13 affected individuals. However, the noted deletion and others in the MEF2A gene failed to segregate with the disease in a subsequent cohort analysis, casting doubt on whether the gene leads to CAD/MI.

Common, Complex Forms of Coronary Artery Disease