Polygenic risk score and coronary artery disease: A meta-analysis of 979,286 participant data
Thomas A Agbaedeng1, Jean Jacques Noubiap2, Edith Pascale Mofo Mato3
1Centre for Heart Rhythm Disorders, The University of Adelaide, Adelaide, Australia; Centre for Cardiometabolic Experimentation and Innovation, Adelaide, Australia.
Insights
Polygenic risk scores (PRS) significantly increase the risk of coronary artery disease (CAD). PRS improves CAD risk prediction when added to clinical risk scores, aiding in identifying high-risk individuals.
Area of Science:
- Genetics and Genomics
- Cardiovascular Disease Epidemiology
- Biostatistics and Risk Prediction
Background:
- Coronary artery disease (CAD) possesses a substantial genetic component.
- Previous research utilized polygenic risk scores (PRS) to assess CAD risk, but their association requires further characterization.
Purpose of the Study:
- To conduct a meta-analysis to quantify the association between polygenic risk scores (PRS) and the risk of coronary artery disease (CAD).
- To evaluate the predictive performance of various PRS computation methods for incident and prevalent CAD.
- To assess the incremental value of PRS when integrated into existing clinical risk prediction models for CAD.
Main Methods:
- A systematic search of online databases was performed to identify studies reporting PRS and CAD.
- PRS were computed using diverse methodologies including log-odds, pruning/clumping, Lassosum, LDpred, and metaGRS.
- A random-effects meta-analysis was employed to pool reported odds ratios, hazard ratios, and C-indexes with their 95% confidence intervals.
Main Results:
- The meta-analysis included 49 studies with 979,286 participants, revealing a significant association between a 1-SD increase in PRS and adjusted risks for both incident and prevalent CAD.
- Specific PRS methods like PRSmetaGRS (OR: 1.67 [1.57-1.77]) and PRSLDpred (OR: 1.46 [1.26-1.68]) showed strong associations.
- PRS demonstrated predictive capability for incident CAD with C-indexes up to 0.71 and provided modest yet statistically significant improvements in risk prediction when added to clinical scores (1.5%-1.6% increase).
Conclusions:
- Polygenic risk scores are robustly associated with elevated risks of coronary artery disease.
- The findings underscore the potential utility of PRS in identifying individuals at high risk for developing CAD.
- Further prospective studies are recommended to validate and refine the application of PRS in clinical settings for CAD risk stratification.
Background And Aims:
Coronary artery disease (CAD) is a complex disease with a strong genetic basis. While previous studies have combined common single-nucleotide polymorphisms (SNPs) into a polygenic risk score (PRS) to predict CAD risk, this association is poorly characterised. We performed a meta-analysis to estimate the effect of PRS on the risk of CAD.
Methods:
Online databases were searched for studies reporting PRS and CAD. PRS computation was based on log-odds (PRSLN), pruning or clumping and thresholding (PRSP/C + T), Lassosum regression (PRSLassosum), LDpred (PRSLDpred), or metaGRS (PRSmetaGRS). The reported odds ratio (OR), hazard ratio (HR), C-indexes and their corresponding 95% confidence interval (95% CI) were pooled in a random-effects meta-analysis.
Results:
Forty-nine studies were included (979,286 individuals). There was a significant association between 1-standard deviation [SD] increment in PRS and adjusted risks of both incident and prevalent CAD (OR [95% CI]: 1.67 [1.57-1.77] for PRSmetaGRS, 1.46 [1.26-1.68] for PRSLDpred). The risk of incident CAD was highest for PRSP/C + T (HR [95% CI]: 1.49 [1.26-1.78]), PRSmetaGRS (1.37 [1.27-1.47]), and PRSLDpred (1.36 [1.31-1.42]). Analysis of model performance demonstrated that PRS predicted incident CAD with C-index of up to 0.71. Importantly, addition of PRS to clinical risk scores resulted in modest but statistically significant improvements in CAD risk prediction, with 1.5% observed for PRSP/C + T (p < 0.001) and 1.6% for PRSLDpred (p < 0.001).
Conclusions:
Polygenic risk score is strongly associated with increased risks of CAD. Future prospective studies should explore the usefulness of polygenic risk scores for identifying individuals at a high risk of developing CAD.
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