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Cardiovascular disease is the leading cause of death in the United States. Considerable progress has been made in the past 50 years to define, identify, and modify risk factors for cardiovascular disease (e.g., hypertension, dyslipidemia, obesity, type 2 diabetes, cigarette smoking, and physical inactivity) and to develop treatments, such as coronary care units, percutaneous coronary interventions, and beta-blockers. These efforts have resulted in an age-adjusted decline in cardiovascular mortality.1 In addition, it is now possible to detect subclinical disease by means of blood biomarker testing2 or imaging measurements3 years before the onset of symptoms or other clinical manifestations.4 Despite this progress, mechanisms that underlie individual differences in the presentation and pathophysiological features of cardiovascular disease are poorly understood. In this article, we review genetic and genomic studies in cardiovascular medicine that have helped to elucidate some of these mechanisms during the past decade (Figure 1, and
Mendelian and Candidate-Gene Studies
Ten years ago, the draft sequence of the human genome, which was produced by scientists working on the Human Genome Project5 and others,6 was first described, leading to an expansion in the understanding of genetic contributions to cardiovascular disease. Before the Human Genome Project, many genes associated with mendelian cardiovascular disease had been identified.7 These forms of cardiovascular disease are rare and constitute a minority of clinical cardiovascular diseases. Genetically, they are simple in that a mutation in a single gene is sufficient to cause disease, so mendelian disease is said to be monogenic. Examples include forms of premature myocardial infarction, dilated and hypertrophic cardiomyopathy, heart failure, arrhythmogenic right ventricular dysplasia, the long-QT syndrome, and aortic aneurysms.7 Recessive mutations underlie familial forms of cardiovascular risk factors, such as hypertension, hypercholesterolemia, and type 2 diabetes. Knowledge obtained through the identification of genes associated with mendelian disease has led to breakthrough discoveries in mechanisms of cardiovascular disease and its treatment. A compelling illustration is the Nobel-Prize–winning discovery that mutations affecting the low-density lipoprotein (LDL) receptor cause hypercholesterolemia and early-onset myocardial infarction, which led to LDL cholesterol–lowering therapies that reduce the risk of cardiovascular events.8
Genomics of Cardiovascular Risk and Disease
Role of Genomewide Association Studies