Integration of a polygenic score into guideline-recommended prediction of cardiovascular disease

Abstract

Background and aims: It is not clear how a polygenic risk score (PRS) can be best combined with guideline-recommended tools for cardiovascular disease (CVD) risk prediction, e.g. SCORE2.

Methods: A PRS for coronary artery disease (CAD) was calculated in participants of UK Biobank (n = 432 981). Within each tenth of the PRS distribution, the odds ratios (ORs)-referred to as PRS-factor-for CVD (i.e. CAD or stroke) were compared between the entire population and subgroups representing the spectrum of clinical risk. Replication was performed in the combined Framingham/Atherosclerosis Risk in Communities (ARIC) populations (n = 10 757). The clinical suitability of a multiplicative model 'SCORE2 × PRS-factor' was tested by risk reclassification.

Results: In subgroups with highly different clinical risks, CVD ORs were stable within each PRS tenth. SCORE2 and PRS showed no significant interactive effects on CVD risk, which qualified them as multiplicative factors: SCORE2 × PRS-factor = total risk. In UK Biobank, the multiplicative model moved 9.55% of the intermediate (n = 145 337) to high-risk group increasing the individuals in this category by 56.6%. Incident CVD occurred in 8.08% of individuals reclassified by the PRS-factor from intermediate to high risk, which was about two-fold of those remained at intermediate risk (4.08%). Likewise, the PRS-factor shifted 8.29% of individuals from moderate to high risk in Framingham/ARIC.

Conclusions: This study demonstrates that absolute CVD risk, determined by a clinical risk score, and relative genetic risk, determined by a PRS, provide independent information. The two components may form a simple multiplicative model improving precision of guideline-recommended tools in predicting incident CVD.

Keywords: Cardiovascular disease; Polygenic risk score; Prevention guidelines; Primary prevention; Risk prediction; SCORE2.

Structured Graphical Abstract

The left panel shows that relative risk related to polygenic disposition [1–10 tenth of the polygenic risk score (PRS) distribution] is independent of having a low, intermediate, or high clinical risk by SCORE2 in the UK Biobank. Thereby, the odds ratio from the PRS (relative risk) can be used as a genetic factor (PRS-factor) to multiply the absolute clinical risk estimate from SCORE2. If this is being done, ∼10% of the intermediate-risk group is being upgraded to a higher total risk (right panel). Subgroups that were genetically upgraded had incident event rates that were similar to those in the original high-risk groups and substantially increased the overall numbers of individuals correctly assessed to be at high risk. CVD, cardiovascular disease.

Figure 1

Odds ratios (PRS-factors) in the entire study population and subgroups carrying traditional risk factors. The figure shows the distribution of the PRS-factor, measured as mean CVD ORs, along PRS tenths in UK Biobank. The fifth/sixth groups were taken as the reference (OR = 1.0). The figure shows within one tenth of the PRS little (non-significant) variation between the entire set and subgroups carrying traditional risk factors. OR, odds ratio; CVD, cardiovascular disease; PRS, polygenic risk score

Figure 2

Cardiovascular disease prevalence and PRS-factors in the entire study and risk categories of SCORE2. (A) Cardiovascular disease prevalence along PRS tenths in clinical risk categories of SCORE2 (low, intermediate, and high). The distribution of CVD prevalence in SCORE2 risk categories fits into a Logit model with R² > 0.9. (B) Cardiovascular disease ORs in risk categories of SCORE2 by PRS tenths; the fifth/sixth groups were taken as reference (OR = 1.0). The figure shows within one tenth of the PRS little (non-significant) variation of the ORs, irrespectively of SCORE2 risk categories, albeit the CVD prevalence differs significantly between low- and high-risk categories (A). OR, odds ratio; CVD, cardiovascular disease; PRS, polygenic risk score

Figure 3

Sankey diagrams visualizing reclassification by PRS-factor. The figure shows the subgroups which were genetically upgraded (PRS-factor > 1) from a lower risk category of SCORE2 to a higher risk category based on ‘SCORE2 × PRS-factor’ in UK Biobank (left) and Framingham/ARIC (right) populations. The left side of two Sankey plots shows CVD incidence of the original groups of SCORE2, and the right side shows CVD incidence of subgroups genetically upgraded by ‘SCORE2 × PRS-factor’. CVD, cardiovascular disease. *The low incidence rate of high-risk category of SCORE2 in Framingham/ARIC populations is because of a high number of prevalent cases (n = 130) that had to be excluded for the analysis of incident events and a small sample size (n = 875)