Sex differences in the associations of multidomain risk factor profiles with incident major adverse cardiovascular events

Background Major adverse cardiovascular events (MACE) exhibit sex-specific disparities, but comprehensive analyses of combined genetic and clinical risk factor profiles across sexes remain limited. Methods This prospective cohort study included 397,806 UK Biobank participants (55.1% female) without baseline MACE. Five weighted risk scores [social-demographic, lifestyle, metabolic, clinical comorbidity, polygenic risk score (PRS)] were evaluated for associations with incident MACE via sex-stratified Cox proportional hazards regression, interaction analyses, and population-attributable risk (PAR) assessments. Results Over a median follow-up of 15.6 years, 32,019 participants (8.0%) developed MACE (11.1% males vs. 5.5% females). Social-demographic (Interaction effect: HR 0.91, 95% CI 0.89–0.93), lifestyle (Interaction effect: HR 0.94, 95% CI 0.91–0.97), and clinical comorbidity (Interaction effect: HR 0.85, 95% CI 0.82–0.87) scores exhibited stronger MACE associations in females than males, while males had higher PRS-related risk (Interaction effect: HR 1.07, 95% CI 1.03–1.11, P for interaction < 0.001). Pairwise interaction patterns differed by sex. PRS integration improved MACE prediction in males ( Δ C-statistic = 0.010, P < 0.001) but not in females ( Δ C-statistic = 0.005, P = 0.299). PAR ranking differed: while social-demographic and clinical comorbidity scores remained the top two contributors across sexes, polygenic risk emerged as the third largest contributor in males (15.9%), and unhealthy lifestyle was the third largest in females (15.6%). Conclusions Sex-specific differences in the effects and contributions of risk factor profiles highlight the need for tailored MACE prevention strategies. Polygenic risk provided modest additional discrimination in males, supporting further evaluation of precise cardiovascular risk assessment.