Abstract

In this review, we summarize current knowledge on the genetics of coronary artery disease, based on 10 years of genome-wide association studies. The discoveries began with individual studies using 200K single nucleotide polymorphism arrays and progressed to large-scale collaborative efforts, involving more than a 100 000 people and up to 40 Mio genetic variants. We discuss the challenges ahead, including those involved in identifying causal genes and deciphering the links between risk variants and disease pathology. We also describe novel insights into disease biology based on the findings of genome-wide association studies. Moreover, we discuss the potential for discovery of novel treatment targets through the integration of different layers of ‘omics’ data and the application of systems genetics approaches. Finally, we provide a brief outlook on the potential for precision medicine to be enhanced by genome-wide association study findings in the cardiovascular field.

Introduction

Coronary artery disease (CAD) is a leading cause of death worldwide.1 It represents the manifestation of atherosclerosis in the coronary arteries, which supply the myocardium with oxygen and other nutrients. Atherosclerosis is an inflammatory process that is strongly driven by lipid accumulation during which the coronary artery wall thickens, forming a plaque, eventually leading to reduced blood flow and myocardial ischaemia.2 The major sequelae of CAD include angina, myocardial infarction (MI), arrhythmias, heart failure, and sudden cardiac death. CAD has a complex aetiology, and various environmental factors, including cigarette smoking, sedentary lifestyle, unhealthy diet and obesity, and disease predisposition.3 These lifestyle-related factors can lead to type 2 diabetes, hypercholesterolaemia and arterial hypertension, which are key risk factors for CAD. In addition, the influence of heritability on CAD susceptibility has been recognized for many years4 and accounts for 40– ۵۰% of cases.5 Although the inherited CAD risk is particularly evident in large families with multiple affected members,6 decade ago only mutations in the LDL receptor gene were reproducibly linked to the disease.