APOE Genotype and Statin Response: Evidence From the UK Biobank and All of Us Program

Abstract

APOE genotype may affect statin response. Using UK Biobank (UKB) and All of Us (AoU) data, we aimed to investigate associations between APOE genotype, statin use, and key health outcomes. Our analysis included UKB baseline data and linked mortality records (389,843-452,189 participants), and electronic health records (EHR) from 45,515 UKB and 35,562 AoU participants. Multivariable regression and Cox models assessed lipid biomarkers, all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE). In UKB, ε3ε4 (HR: 1.08, 95% CI: 1.01-1.15) and ε4ε4 (HR: 1.54, 95% CI: 1.33-1.78) carriers had higher all-cause mortality risk. In AoU, only ε4ε4 carriers showed increased risk (HR: 1.64, 95% CI: 1.08-2.49). Cardiovascular mortality was assessed only in UKB, where ε4ε4 carriers had an increased risk (HR: 1.30, 95% CI: 1.01-1.68). Mortality associations in UKB EHR data were consistent with those from baseline data and linked mortality records (e.g., ε4ε4 genotype: all-cause mortality HR: 1.51, 95% CI: 1.41-1.62; cardiovascular mortality HR: 1.54, 95% CI: 1.33-1.77). However, the statin:APOE interaction term included in the baseline analysis was not statistically significant. In AoU, changes in HDLC, LDLC, and triglycerides were associated with reduced all-cause mortality risk. No significant MACE associations were observed in either cohort. This study reaffirms that APOE ε4 genotype increases mortality risk, including in statin-treated patients, and could therefore be used to inform enhanced monitoring or medication review in these patients.

Keywords: APOE genotype; All of Us Research Program; UK Biobank; lipid response; major adverse cardiovascular events; mortality; statins.

FIGURE 1

Flowchart for included participants. Bold values represent the total number of participants at each stage. APOE, apolipoprotein E; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; MACE, major adverse cardiovascular events.

FIGURE 2

Associations between APOE genotype, statin use, and lipid biomarkers in the UK Biobank baseline analysis. This figure shows the median adjusted lipid biomarkers (top row), adjusted net changes (second row), adjusted percent changes (third row), and adjusted net change relative to the ε3ε3 genotype (bottom row) across different APOE genotypes. The lipid biomarkers analyzed include apolipoprotein A (ApoA), apolipoprotein B (ApoB), HDL cholesterol (HDLC), LDL cholesterol (LDLC), lipoprotein A (Lipo(a)), total cholesterol (TC), and triglycerides (TG). In the bottom row, for ApoA and HDLC (increase beneficial), positive values indicate more benefit with statins relative to the ε3ε3 genotype, while for other biomarkers (reduction beneficial), negative values indicate more benefit. Units for each biomarker are specified in their respective plots, with error bars representing 95% confidence intervals. Adjusted biomarker values are based on predictions from models adjusted for age at recruitment, sex, body mass index, smoking status, alcohol consumption, race, physical activity level, genotyping array, Townsend index, the first 10 principal components of genetic ancestry, and the interaction between APOE genotype and statin use.

FIGURE 3

Associations between APOE genotype, statin use, and mortality outcomes in the UK Biobank baseline analysis. This figure presents hazard ratios and 95% confidence intervals (CIs) for (A) all‐cause death and (B) cardiovascular death, stratified by statin use, apolipoprotein E (APOE) genotype, and the statin:APOE interaction. Genotype effect estimates reflect associations across the entire cohort, including both statin users and nonusers. The analysis adjusts for multiple covariates, including age, sex, body mass index, race, smoking status, alcohol consumption, physical activity, Townsend deprivation index, systolic and diastolic blood pressure, use of antihypertensive medications, diabetes mellitus history, cardiovascular disease history, genotyping array, and the first 10 principal components of genetic ancestry.

FIGURE 4

Associations between APOE genotype and clinical outcomes in the UK Biobank Electronic Health Records (statin‐treated patients). This figure shows hazard ratios and 95% confidence intervals for three clinical outcomes: (A) All‐cause death, (B) Cardiovascular death, and (C) Major adverse cardiovascular events. The analyses are adjusted for the following covariates: age, sex, histories of hypertension, diabetes mellitus, and cardiovascular disease, data provider, type and strength of statin, genotyping array, and the first 10 principal components of genetic ancestry. APOE, apolipoprotein E.

FIGURE 5

Associations between APOE genotype and clinical outcomes in the All of US Program (statin‐treated patients). This figure shows hazard ratios and 95% confidence intervals for three clinical outcomes: (A) All‐cause death and (B) Major adverse cardiovascular events. The analyses are adjusted for the following covariates: age, sex, histories of hypertension, diabetes mellitus, and cardiovascular disease, type and strength of statin, and the first 10 principal components of genetic ancestry. APOE, apolipoprotein E.

FIGURE 6

Associations between net changes (mmol/L) in lipid biomarkers and all‐cause mortality in statin‐treated patients. Panels A and B show hazard ratios (HRs) with 95% confidence intervals (CIs) for the UK Biobank and All of Us cohorts, respectively. Net changes in HDLC were calculated as posttreatment minus pretreatment biomarker levels, meaning HRs represent the risk associated with a 1 mmol/L increase in HDLC (HR < 1 indicates a beneficial effect). For all other biomarkers, net changes were calculated as pretreatment minus posttreatment levels, so HRs reflect the risk associated with a 1 mmol/L reduction (HR < 1 indicates a beneficial effect). Analyses were adjusted for age, sex, histories of hypertension, diabetes mellitus, and cardiovascular disease, data provider (UK Biobank), type and strength of statin, genotyping array (UK Biobank), APOE genotype, and the first 10 principal components of genetic ancestry. APOE, apolipoprotein E; HDLC, high‐density lipoprotein cholesterol; LDLC, low‐density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides.