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Clinical validation of a statin-benefit polygenic score using real-world cohorts of primary prevention participants
Tanushree Haldar1, Kyung Min Lee2, Craig C Teerlink2,3
1Department of Clinical Pharmacy, University of California San Francisco, San Francisco, CA, USA.
Insights
Including sub-genome-wide variants in coronary artery disease polygenic risk scores enhances statin effectiveness for preventing major adverse cardiovascular events. This approach improves risk prediction for primary prevention strategies.
Area of Science:
- Cardiovascular Genetics
- Pharmacogenomics
- Biostatistics
Background:
- Polygenic risk scores (PRS) from genome-wide association studies (GWAS) are linked to statin effectiveness in coronary artery disease (CAD).
- The utility of including variants below genome-wide significance thresholds in PRS for predicting statin response is less understood.
Purpose of the Study:
- To investigate the association between CAD PRS, incorporating sub-genome-wide significant variants, and the effectiveness of statins in primary prevention of major adverse cardiovascular events (MACE).
- To compare PRS models with and without sub-genome-wide variants for predicting statin benefit.
Main Methods:
- Generated CAD PRS for participants without prior myocardial infarction from three large biobanks (All of Us, AGHA, MVP).
- Utilized three PRS: metaGRS and PRS2022 (genome-wide and sub-genome-wide variants), and 164SNP (genome-wide significant variants only).
- Employed Cox regression and meta-analysis to assess statin effectiveness across PRS strata.
Main Results:
- Statin use showed a significantly stronger association with reduced MACE risk in individuals with high PRS compared to low PRS for PRS2022 (P=2.3E-3) and metaGRS (P=.02) scores.
- The 164SNP PRS did not yield a statistically significant interaction (P=.08), indicating less robust prediction.
Conclusions:
- Incorporating sub-genome-wide variants into CAD PRS enhances the prediction of statin relative risk reduction for primary prevention.
- These findings suggest potential for improved clinical utility of PRS in personalized cardiovascular risk management.
Background:
Polygenic risk scores derived from coronary artery disease genome-wide association studies are associated with statin relative risk reduction.
Objective:
Examine the relationship between coronary artery disease polygenic risk scores that include variants below thresholds of genome-wide significance and statin primary prevention of major adverse cardiovascular events.
Methods:
We generated coronary artery disease polygenic risk scores for participants with no past evidence of myocardial infarction from three electronic health record-linked genetic biobanks: All of Us Research Program, Genetic Epidemiology Research on Adult Health and Aging, and the Million Veteran Program. We scored each participant using three different polygenic risk scores: two with both genome-wide and sub-genome-wide significant variants (metaGRS and PRS2022) and one with only variants meeting genome-wide significance (164SNP). We used covariate-adjusted Cox regression models to compare risk of major adverse cardiovascular events between statin users and nonusers matched on age, sex, smoking status, type 2 diabetes mellitus, and hypertension within strata defined by polygenic risk. For the primary analysis, we performed a meta-analysis across the three cohorts for the delta hazard ratio of statin effectiveness between high and low polygenic risk.
Results:
Across all cohorts, statin use was more strongly associated with reduced risk of major adverse cardiovascular events among participants with no myocardial infarction at index in the highest versus lowest polygenic risk score group for the PRS2022 (interaction beta 0.19, standard error 0.07, interaction P=2.3E-3) and metaGRS (interaction beta 0.14, standard error 0.07, interaction P=.02) scores. However, the association was not statistically significant (interaction beta 0.09, standard error 0.07, interaction P=.08) for the 164SNP risk score.
Conclusions:
We demonstrated that the association between coronary artery disease polygenic risk scores and statin relative risk reduction can by enhanced with the inclusion of sub-genome-wide variants, paving the way for more research to establish clinical utility.
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