Celiac disease increases the risk of pulmonary arterial hypertension: A multivariable Mendelian randomization and mediation analysis

Celiac disease (CeD) has been implicated in several autoimmune and vascular disorders, but its causal role in pulmonary arterial hypertension (PAH) remains uncertain. Summary-level genome-wide association study data for all traits were obtained from the FinnGen consortium and the genome-wide association study catalog, 2 publicly accessible databases integrating genetic data with health registry information. A 2-sample Mendelian randomization (MR) approach was employed to evaluate the causal effect of CeD on PAH. Univariable MR was conducted initially, and the results were validated through meta-analysis based on 2 independent cohorts. To control for possible confounding influences, multivariable MR was applied with adjustments for obesity and smoking. Mediation analyses were performed to determine whether autoimmune disorders mediated the observed association. Heterogeneity and pleiotropy were assessed to ensure the robustness of the findings. A significant causal association between CeD and PAH was identified in the univariable MR analysis (discovery cohort: odds ratio OR of inverse-variance weighted IVW OR IVW , 1.148; 95% confidence interval CI, 1.027–1.282; P = .015; replication cohort: OR IVW , 1.112; 95% CI, 1.043–1.186; P = .001), and this relationship was further supported by the meta-analysis of both cohorts (OR IVW , 1.136; 95% CI, 1.065–1.212; P .050). Genetic evidence supports that CeD increases the risk of PAH, with systemic lupus erythematosus potentially acting as a mediator. These findings provide new insights into shared autoimmune mechanisms underlying PAH and suggest that immune regulation may represent a potential therapeutic target.