Integrated Polygenic Tool Substantially Enhances Coronary Artery Disease Prediction

Abstract

Background: There is considerable interest in whether genetic data can be used to improve standard cardiovascular disease risk calculators, as the latter are routinely used in clinical practice to manage preventative treatment.

Methods: Using the UK Biobank resource, we developed our own polygenic risk score for coronary artery disease (CAD). We used an additional 60 000 UK Biobank individuals to develop an integrated risk tool (IRT) that combined our polygenic risk score with established risk tools (either the American Heart Association/American College of Cardiology pooled cohort equations [PCE] or UK QRISK3), and we tested our IRT in an additional, independent set of 186 451 UK Biobank individuals.

Results: The novel CAD polygenic risk score shows superior predictive power for CAD events, compared with other published polygenic risk scores, and is largely uncorrelated with PCE and QRISK3. When combined with PCE into an IRT, it has superior predictive accuracy. Overall, 10.4% of incident CAD cases were misclassified as low risk by PCE and correctly classified as high risk by the IRT, compared with 4.4% misclassified by the IRT and correctly classified by PCE. The overall net reclassification improvement for the IRT was 5.9% (95% CI, 4.7-7.0). When individuals were stratified into age-by-sex subgroups, the improvement was larger for all subgroups (range, 8.3%-15.4%), with the best performance in 40- to 54-year-old men (15.4% [95% CI, 11.6-19.3]). Comparable results were found using a different risk tool (QRISK3) and also a broader definition of cardiovascular disease. Use of the IRT is estimated to avoid up to 12 000 deaths in the United States over a 5-year period.

Conclusions: An IRT that includes polygenic risk outperforms current risk stratification tools and offers greater opportunity for early interventions. Given the plummeting costs of genetic tests, future iterations of CAD risk tools would be enhanced with the addition of a person's polygenic risk.

Keywords: coronary artery disease; genetic epidemiology; genetics; primary prevention; risk factors.

Figure 1.

Cumulative incidence of coronary artery disease (CAD) in UK Biobank incident cases in group III. A, All of group III. B, Group III stratified into 4 subgroups according to age (45–54- and 55–69-y-old age ranges) and sex. Individuals are further stratified by polygenic risk score (PRS)–defined risk into the top 5% of PRS risk (red), the median 40% to 60% distribution of risk (blue), and the bottom 5% of risk distribution (green).

Figure 2.

Cumulative incidence of coronary artery disease (CAD) in the subgroup of 40- to 54-y-old men in group III. Individuals are stratified by pooled cohort equations (PCE) and integrated risk tool (IRT)–defined risk (above/below the 7.5% threshold) into those predicted to be high risk by both PCE and IRT (red), those up-classified to high risk by IRT (purple), those down-classified to low risk by IRT (blue), and those predicted to be at low risk by both PCE and IRT (green).

Figure 3.

Model discrimination and net reclassification improvement for the integrated risk tool (IRT) compared with pooled cohort equations (PCE). A, Harrell’s C overall and across age-by-sex subgroups. Blue and red lines refer to IRT and PCE, respectively. Asterisks in x axis labels denote level of significance for the difference in Harrel C (***P<0.001). B, Net reclassification improvement (NRI) for the IRT compared with PCE alone across different age groups in men (blue) and women (red). The bars indicate the 95% CIs.