Coronary artery disease polygenic risk score in patients undergoing coronary angiography and risk of future revascularization

Abstract Background Coronary artery disease (CAD) polygenic risk score (PRS) is a strong predictor of incident CAD. The role of CAD PRS in patients with known or suspected CAD already presenting for invasive coronary angiography remains poorly understood. Purpose We aimed to (i) study the association between CAD PRS and coronary angiography traits, and (ii) determine whether CAD PRS can predict risk of future revascularization after an initial coronary angiogram. Methods Patients who underwent coronary angiography at a single hospital and were part of its biobank were included in the study. Participants were classified into 3 risk groups based on CAD PRS distribution–low (0-20%), intermediate (21-80%), and high (81-100%)–computed from a recently reported PRS comprised of 1,296,172 variants (GPSMult, PGS003725). Revascularization was defined as a composite of coronary artery bypass graft and percutaneous coronary intervention with a 3-month blocking window after the initial angiogram. Associations between coronary stenosis severity and burden, and CAD PRS were assessed using multinomial logistic regression adjusted for age, sex, and genetic ancestry. The cumulative incidence of revascularization was tested using Fine-Gray regression accounting for competing risk of all-cause mortality and compared across CAD PRS strata by log-rank test. Results Among 3,518 participants (29.90% female, mean age 63.29±12.14 years), 2,568 (73%) had angiographic evidence of CAD – 340 (13.24%) mild, 346 (13.47%) moderate, and 1,882 (73.29%) severe. Out of those with CAD, 844 (32.87%) presented with acute coronary syndromes (ACS) and 1,724 (67.13%) with stable CAD. CAD PRS was strongly associated with angiographic presence of CAD (OR 2.62, 95%CI 2.08-3.29) and this did not differ among patients presenting with ACS vs. stable CAD (Fig1A). The association was weakest for mild CAD (OR 1.14, 95%CI 0.77-1.68) and strongest for severe CAD (OR 3.04, 95%CI 2.40-3.84). Besides severity, CAD PRS was also strongly associated with angiographic burden of CAD with the strongest association observed for presence of left main coronary stenosis (OR 2.63, 95%CI 1.86-3.73). Each standard deviation increase in CAD PRS was associated with a 10-point increase in the Gensini score, a continuous measure of angiographic burden of CAD (p<2e-16) (Fig1B). Over a mean follow-up period of 9.26±5.81 years, 659 (18.73%) patients required revascularization at a mean period of 5.31±4.69 years. Risk of revascularization varied dramatically by CAD PRS; HR was 1.64 (95%CI 1.28-2.10, p=8.7e-5) for high vs. low CAD PRS (Fig2). CAD PRS remained predictive of future revascularization even after adjusting for the angiographic burden of CAD at baseline (HR 1.41, 95%CI 1.09-1.82, p=7.9e-3). Conclusion CAD PRS is strongly associated with severity and burden of CAD assessed on coronary angiography and is predictive of future risk of revascularization even after accounting for baseline disease burden.Figure 1.CAD PRS and angiographic traitsFigure 2.CAD PRS and revascularization