Abstract
Uterine fibroids (UF), the most common benign tumors in women, have been associated with cardiovascular disease (CVD) in observational studies, yet causal inference remains unclear due to confounding. This Mendelian randomization (MR) study leveraged genetic variants as instrumental variables (IVs) to evaluate the causal relationship between genetically predicted UF and CVD risk. Exposure data were derived from a UK Biobank genome-wide association study of 462,933 Europeans (5168 UF cases). Outcome data for CVD subtypes were obtained from FinnGen and EBI consortia (sample sizes: 180, 862-977, 323). Fourteen independent single-nucleotide polymorphisms strongly associated with UF (P < 5 × 10⁻⁶) were selected as IVs, pruned for linkage disequilibrium (r2<0.001; F-statistic > 10). The inverse-variance-weighted method was used for primary analysis, supplemented by sensitivity approaches (weighted median, MR-Egger, MR-PRESSO). Robustness was evaluated via Cochran Q test (heterogeneity), MR-Egger intercept (pleiotropy), and leave-one-out analysis. Genetically predicted UF showed no causal effects on ischemic heart disease (OR = 2.00E-02, 95% CI: 2.21E-04 to 2.47E+00, P = .11), heart failure (OR = 5.20E-01, 95% CI = 1.03E-02 to 2.57E+01, P = .74), venous thromboembolism (OR = 1.65E+00, 95% CI: 1.13E-03 to 2.41E+03, P = .89), or stroke (OR = 3.70E-01, 95% CI = 1.82E-03 to 7.48E+01, P = .71). Sensitivity analyses confirmed consistency (all P > .05), with no heterogeneity (Cochran Q P > .05) or horizontal pleiotropy (MR-Egger intercept P > .05). Leave-one-out analysis indicated stable estimates. This MR study found insufficient evidence to support a causal link between UF and CVD, contrasting previous observational reports.