Genetics of coronary artery disease and myocardial infarction

Abstract

Atherosclerotic coronary artery disease (CAD) comprises a broad spectrum of clinical entities that include asymptomatic subclinical atherosclerosis and its clinical complications, such as angina pectoris, myocardial infarction (MI) and sudden cardiac death. CAD continues to be the leading cause of death in industrialized society. The long-recognized familial clustering of CAD suggests that genetics plays a central role in its development, with the heritability of CAD and MI estimated at approximately 50% to 60%. Understanding the genetic architecture of CAD and MI has proven to be difficult and costly due to the heterogeneity of clinical CAD and the underlying multi-decade complex pathophysiological processes that involve both genetic and environmental interactions. This review describes the clinical heterogeneity of CAD and MI to clarify the disease spectrum in genetic studies, provides a brief overview of the historical understanding and estimation of the heritability of CAD and MI, recounts major gene discoveries of potential causal mutations in familial CAD and MI, summarizes CAD and MI-associated genetic variants identified using candidate gene approaches and genome-wide association studies (GWAS), and summarizes the current status of the construction and validations of genetic risk scores for lifetime risk prediction and guidance for preventive strategies. Potential protective genetic factors against the development of CAD and MI are also discussed. Finally, GWAS have identified multiple genetic factors associated with an increased risk of in-stent restenosis following stent placement for obstructive CAD. This review will also address genetic factors associated with in-stent restenosis, which may ultimately guide clinical decision-making regarding revascularization strategies for patients with CAD and MI.

Keywords: Atherosclerosis; Coronary artery disease; Genetics; Genome-wide association study; Heritability; In-stent restenosis; Myocardial infarction.

Figure 1

Atherosclerosis is a multi-decade pathological process involving complex interactions between genetics and environmental factors. The estimated heritability of CAD and MI is 50% to 60%. The heritability of each individual risk factor is indicated as a %. CAD: Coronary artery disease; MI: Myocardial infarction.

Figure 2

Chromosome map of genes reported to be causal for, susceptible to and associated with coronary artery disease and myocardial infarction in the literature. Genes in red are causal genes for monogenic familial CAD and MI. CAD: Coronary artery disease; MI: Myocardial infarction.

Figure 3

The balance between athero-protective (A) and pro-atherogenic (B) factors involved in the development of atherosclerosis. Obstructive atherosclerotic arterial disease results from the loss of balance between these two factors. A: A list of factors and processes that provide protective effects against atherogenesis; B: A list of factors and processes that promote atherogenesis. HDL: High-density lipoprotein; LDL: Low-density lipoprotein.