Genetic Risk Stratification: A Paradigm Shift in Prevention of Coronary Artery Disease

Abstract

Coronary artery disease (CAD) is a pandemic disease that is highly preventable as shown by secondary prevention. Primary prevention is preferred knowing that 50% of the population can expect a cardiac event in their lifetime. Risk stratification for primary prevention using the American Heart Association/American College of Cardiology predicted 10-year risk based on conventional risk factors for CAD is less than optimal. Conventional risk factors such as hypertension, cholesterol, and age are age-dependent and not present until the sixth or seventh decade of life. The genetic risk score (GRS), which is estimated from the recently discovered genetic variants predisposed to CAD, offers a potential solution to this dilemma. The GRS, which is derived from genotyping the population with a microarray containing these genetic risk variants, has indicated that genetic risk stratification based on the GRS is superior to that of conventional risk factors in detecting those at high risk and who would benefit most from statin therapy. Studies performed in >1 million individuals confirmed genetic risk stratification is superior and primarily independent of conventional risk factors. Prospective clinical trials based on risk stratification for CAD using the GRS have shown lifestyle changes, physical activity, and statin therapy are associated with 40% to 50% reduction in cardiac events in the high genetic risk group (20%). Genetic risk stratification has the advantage of being innate to an individual's DNA, and because DNA does not change in a lifetime, it is independent of age. Genetic risk stratification is inexpensive and can be performed worldwide, providing risk analysis at any age and thus has the potential to revolutionize primary prevention.

Keywords: ACC, American College of Cardiology; AHA, American Heart Association; ANRIL, antisense non-coding RNA in the INK4 Locust; CAD, coronary artery disease; GRS, genetic risk score; GWAS, genome-wide association study; LDL-C, low-density lipoprotein cholesterol; MR, Mendelian randomization; SNP, single nucleotide polymorphism; bp, base pair; cardiovascular genetics; coronary artery disease; genetic risk score for CAD; genome-wide association studies; prevention of CAD.

Graphical abstract

Central Illustration

The Journey From Gene Discovery to Clinical Application A brief summary from genetics to clinical applicationis shown. Genome wide association studies made possible an unbiased search for genetic variants predisposing to coronary artery disease (CAD). The total risk burden was summarized in a single number referred to as the Genetic Risk Score (GRS). The GRS was utilized to stratify for risk of CAD. Prospective clinical trials showed lifestyle changes and drug therapy decreased genetic risk by 40% to 50%.

Figure 1

Suggested Pathways for Involvement of Genetic Risk Variants Various organs or pathways associated with 163 mapped genetic risk loci for CAD are shown in the figure. Reprinted with permission by Erdmann et al. (45). CAD = coronary artery disease.

Figure 2

Genetic Risk Stratification for CAD A saliva or blood sample can be used to extract the DNA. The DNA is genotyped for risk variants known to predispose to CAD. The genetic risk score is calculated as a single number which is the basis to divide the population into low, intermediate, and high risk. The percentage is an estimate based on previous data. Abbreviation as in Figure 1.