Genetic Risk Factors of Coronary Artery Disease

Abstract

Detecting genetic risk factors for better targeting of statin administration can further enhance the benefit of this therapy. Coronary artery disease (CAD) is a polygenic disorder with multiple genetic variants. A composite of some of these variants could ascertain the risk of both incident and recurrent CAD events and help in the diagnosis of patients at greater risk who could get greater clinical benefit from statin treatment [1]. The role of genetic risk factors in CAD has become more relevant with the discovery of the proprotein convertase subtilisin kexin type 9 (PCSK9) enzyme, which is responsible for regulating cholesterol metabolism [2, 3]. Gain-of-function mutations of the PCSK9 gene may be associated with increased cholesterol and increased risk of CVDs, whereas loss-of-function mutations are linked to lower blood cholesterol and a reduction of CVDs risk without any known adverse effects [2-5]. This included a community-based landmark assessment employing multiple studies involving 48,421 individuals and 3,477 events [1]. This analysis examined the association of a genetic risk score based on 27 genetic variants with either incident or recurrent CAD, adjusting for traditional clinical risk factors. All subjects were divided into low (quintile 1), intermediate (quintiles 2–4), and high (quintile 5) genetic risk categories, to demonstrate a significant gradient in risk for incident or recurrent CAD. The multivariable-adjusted hazard ratio for CAD events for the intermediate genetic risk category was 1.34 (95% CI: 1.22–1.47, p < 0.0001) and that for the high genetic risk category was 1.72 (1.55–1.92, p < 0.0001) compared with the low genetic risk subjects [1]. There was a significant gradient (p = 0.0277) of increasing relative risk across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Absolute risk reduction from statin treatment was greater in some patients with higher genetic risk categories (p = 0.0101). In the primary prevention trials, the number needed to treat to prevent one CAD event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in the JUPITER, and 57, 47, and 20, respectively, in the ASCOT trial. We can conclude from this analysis that a genetic risk score can identify the high risk subjects with increased risk for both incident and recurrent CAD events. Patients with the highest burden of genetic risk obtained the greatest relative and absolute clinical benefit from statin treatment. We propose that patients with highest genetic risk might also get greatest benefit by treatment with PCSK9 inhibitors.