<i>APOE</i> ε4 Allele and Methylation Patterns Linked to Cardiovascular Outcomes in Women With Breast Cancer

DNA methylation affects gene expression. While the Apolipoprotein E (<i>APOE</i>) genotype impacts cardiovascular risk, <i>APOE</i> methylation impact remains unknown, particularly in women with breast cancer (BC). This study explored associations of <i>APOE</i> methylation with hypertension history and cardiovascular fitness (CVF) and whether <i>APOE</i> 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 <i>APOE</i> 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 <i>APOE</i> genotype were interaction terms for longitudinal analyses. This study included 102 women (Mean = 62 yrs). <i>APOE</i>ε4 carriers had increased methylation of cg06750524 (<i>p =</i> 0.04) and cg19514613 (<i>p =</i> 0.03), but lower methylation of cg21879725 (<i>p =</i> 0.04). Increased cg06750524 methylation was associated with higher hypertension odds (<i>p =</i> 0.022, OR = 2.813) and lower VO₂max/kg/min and METs (<i>p =</i> 0.005). Increased cg05501958 methylation (M = 4.539, SD = 0.17) was associated with lower hypertension odds (<i>p =</i> 0.02, OR = 0.035) and higher VO₂max/kg/min and METs (<i>p =</i> 0.022). Neither <i>APOE ε4</i> nor baseline methylation moderated exercise effects. <i>APOE</i> methylation, differentially by ε4 carriage, may impact cardiovascular outcomes and serve as a biomarker of risk in women with BC.