Background: We aimed to evaluate associations between polygenic risk score (PRS), and lifestyle with cardiovascular risk factors (CVRFs) assessed as continuous phenotypes (LDL, HDL, triglycerides, fasting glucose [FG], systolic [SBP] and diastolic blood pressure [DBP]) among childhood cancer survivors. Methods: Participants included 2,347 White survivors (mean age=35.5 (±9.3) years) enrolled in the St. Jude Lifetime Cohort. Phenotype-specific PRS (derived from general population) were divided into tertiles and survivors classified as being at low-, intermediate-, or high-genetic risk. Lifestyle, classified as good, intermediate, or poor, was assessed based on four factors (smoking [yes/no], physical activity [meeting CDC guidelines for physical activity], diet quality [Healthy Eating Index score >59], and obesity [BMI≥30kg/m²]). A general linear model was created for each CVRF in which the effect of lifestyle (good, intermediate, poor) was examined within genetic risk group (low, intermediate, high), adjusting for sex, age, cancer therapies and current medication use. Results: The table shows worsening CVRF profiles associated with declining lifestyle and with increasing genetic risk. For example, among survivors with poor lifestyle-high genetic risk, SBP and DBP were higher on average by 14 (95% CI = 9-18) and 9 (95% CI = 6-12) mmHg respectively, compared to survivors with good lifestyle-low genetic risk. In analyses restricted to survivors with high genetic risk, mean SBP (7, 95% CI=2-12) mmHg, DBP (4, 95% CI=1-7) mmHg, triglyceride (61, 95% CI=5-117) mg/dL, and FG (7, 95% CI=4-10) mg/dL values were higher among survivors with poor versus good lifestyle, while mean HDL was lower (-13, 95% CI= -8- -18) mg/dL. Conclusions: While the risk of CVRFs among cancer survivors are associated with high genetic risk and cancer therapies, healthy lifestyle choices may partially ameliorate perturbations in CVRFs even among those with high genetic risk. Our findings highlight the importance of developing interventions targeting modifiable behaviors in this high-risk population.

*p<0.05.