Synergistic effects of female-specific conditions and genetic risk on cardiometabolic disease: a cohort study

Background The role of female-specific factors in the occurrence and progression of cardiometabolic disease (CMD) across different genetic risks remains incompletely clear. This study aimed to comprehensively assess the association of female-specific factors with the occurrence and progression of CMD. Methods This was a prospective cohort study of 150 413 female individuals from the UK Biobank. The female-specific factors in this study included premature menopause, adverse pregnancy outcomes, early or late menarche, multiparity, infertility, use of oral contraceptive or hormone therapy and autoimmune diseases, and a weighted female-specific risk score (FSRS, ranging from 0 to 6) was constructed. We analysed the association of female-specific factors with the occurrence and progression of CMD across genetic risks. Results A total of 16 636 CMD events were documented after a median follow-up of 13.7 years. A one-point increase in FSRS was associated with a 24% higher risk of incident CMD, with persistent association with progression to first CMD, cardiometabolic multimorbidity and mortality. Female-specific factors and genetic susceptibility were synergistically associated with a higher risk of CMD (p Interaction <0.001). Compared with the group with low female-specific and genetic risks, the group with high female-specific and genetic risk had a 243% increased risk of CMD. FSRS had a relatively high predictive value for CMD, especially in the group with higher genetic risks, and modestly improved the performance of two recommended cardiovascular algorithms. Phenotypic ageing, inflammation, metabolic factors, renal function and oestradiol collectively explained 21.6% of the association between FSRS and CMD. Conclusions Female-specific health factors significantly contribute to CMD risk and interact with genetic susceptibility. Incorporating these factors into risk assessment models could enhance predictive accuracy, particularly for women with high genetic risk.