Abstract
BACKGROUND: While extensive research highlighted the involvement of metabolism and immune cells in female reproductive diseases, causality remains unestablished. METHODS: Instrumental variables for 486 circulating metabolites (N = 7824) and 731 immunophenotypes (N = 3757) were derived from a genome-wide association study (GWAS) meta-analysis. FinnGen contributed data on 14 female reproductive disorders. A bidirectional two-sample Mendelian randomization study was performed to determine the relationships between exposures and outcomes. The robustness of results, potential heterogeneity, and horizontal pleiotropy were examined through sensitivity analysis. RESULTS: High levels of mannose were found to be causally associated with increased risks of gestational diabetes (GDM) (OR [95% CI], 6.02 [2.85-12.73], p = 2.55 × 10(-6)). A genetically predicted elevation in the relative count of circulating CD28(-)CD25(++)CD8(+) T cells was causally related to increased female infertility risk (OR [95% CI], 1.26 [1.14-1.40], p = 1.07 × 10(-5)), whereas a high absolute count of NKT cells reduced the risk of ectopic pregnancy (OR [95% CI], 0.87 [0.82-0.93], p = 5.94 × 10(-6)). These results remained consistent in sensitivity analyses. CONCLUSIONS: Our study supports mannose as a promising GDM biomarker and intervention target by integrating metabolomics and genomics.