Genetic Mediators of Celiac Disease and Premature Ovarian Failure: Hypothyroidism and Systemic Lupus Erythematosus

ABSTRACT Background Observational studies suggested celiac disease (CD) possibly be a risk factor for premature ovarian failure (POF). However, causality remains unclear. And hypothyroidism and systemic lupus erythematosus may be the mediating factors. Methods We performed 2‐sample Mendelian randomization (2SMR) to infer a causal relationship between CD and POF using genome‐wide association study summary data obtained from IEU OpenGWAS database and FinnGen R12 database. Inverse‐variance weighted method was used as the main analysis of MR. Heterogeneity was measured based on Cochran's Q value. We used the Two‐Step MR to analyze whether hypothyroidism and SLE are mediators of the causal relationship between CD and POF. Summary level data of the hypothyroidism and SLE were obtained from IEU OpenGWAS. Results Genetically predicted CD may increase the risk of POF by 16% (odds ratio [OR]: 1.16, 95% CI: 1.06–1.26, p = 0.001). Hypothyroidism and SLE could mediate 13.46% and 26.36% of the association between CD and POF, respectively ( p = 0.038, p = 0.025). Conclusions Our study revealed that CD has a positive contribution effect on POF. CD can elevate the risk of POF by 16%. Besides, hypothyroidism and SLE played a partial mediating role in the causal relationship between the two.