APOE ε4 Allele and Methylation Patterns Linked to Cardiovascular Outcomes in Women With Breast Cancer

DNA methylation affects gene expression. While the Apolipoprotein E (APOE) genotype impacts cardiovascular risk, APOE methylation impact remains unknown, particularly in women with breast cancer (BC). This study explored associations of APOE methylation with hypertension history and cardiovascular fitness (CVF) and whether APOE genotype and methylation moderate exercise effects over 6 months. This study leveraged data from a 6-month exercise randomized clinical trial in postmenopausal women with BC. Using peripheral blood, methylation M-values (Illumina Infinium Methylation EPIC Beadchip) and 13 CpG sites within and 2kb 5' and 3' to APOE were abstracted post data quality checks. Outcome variables: self-reported hypertension and CVF (peak oxygen consumed per kilogram per minute [VO₂max/kg/min] and peak metabolic equivalents [METs] through graded exercise testing). Participants completed 150 min/week of aerobic exercise or usual care for 6 months. Logistic and linear regression examined associations between CpG M-values and hypertension, VO₂max/kg/min and METs. Baseline M-value and APOE genotype were interaction terms for longitudinal analyses. This study included 102 women (Mean = 62 yrs). APOEε4 carriers had increased methylation of cg06750524 (p = 0.04) and cg19514613 (p = 0.03), but lower methylation of cg21879725 (p = 0.04). Increased cg06750524 methylation was associated with higher hypertension odds (p = 0.022, OR = 2.813) and lower VO₂max/kg/min and METs (p = 0.005). Increased cg05501958 methylation (M = 4.539, SD = 0.17) was associated with lower hypertension odds (p = 0.02, OR = 0.035) and higher VO₂max/kg/min and METs (p = 0.022). Neither APOE ε4 nor baseline methylation moderated exercise effects. APOE methylation, differentially by ε4 carriage, may impact cardiovascular outcomes and serve as a biomarker of risk in women with BC.