APOEGenotype and Statin Response: Evidence from Electronic Health Records in the UK Biobank and All of Us Research Program

Abstract

Introduction: APOE genotype may affect statin response. We investigated the relationship between APOE genotype and key outcomes in statin users using UK Biobank (UKB) and All of Us (AoU) data. Methods: We analysed electronic health records from up to 45,515 UKB participants and 35,562 AoU participants. Using multivariable linear regression and Cox proportional hazards models, we assessed associations between APOE genotype and outcomes, including lipid biomarkers, all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE). Results: After Bonferroni correction, significant changes in HDLC and triglyceride levels were observed in both cohorts (P < 0.01) following statin initiation. For all-cause mortality, significant associations were found in the UKB cohort, with ε3ε4 (HR: 1.08, 95% CI: 1.01-1.15) and ε4ε4 (HR: 1.54, 1.33-1.78) carriers showing higher risk compared to the reference ε3ε3 genotype. In the AoU cohort, only ε4ε4 carriers showed an increased risk (HR: 1.64, 1.08-2.49). Cardiovascular-related mortality was assessed in only the UKB cohort, with ε4ε4 carriers having an increased risk (HR: 1.30, 1.01-1.68). In the AoU cohort, lipid level changes were significantly associated with reduced all-cause mortality risk: HDLC (median increase of 0.03 mmol/L, HR: 0.26 [0.16-0.41] per mmol/L), LDLC (median reduction of 0.82 mmol/L, HR: 0.82 [0.69-0.97] per mmol/L), and triglycerides (median reduction of 0.10 mmol/L, HR: 0.79 [0.72-0.87] per mmol/L). No significant associations with MACE were observed in either cohort. Conclusion: This study re-affirms that APOE genotype significantly impacts statin response, highlighting the need to integrate genetics into personalized treatment regimens.