Unlocking New Treatment Horizons for Celiac Disease: PRKCD Revealed as a Promising Target through Mendelian Randomization.

Introduction: Celiac Disease (CeD) is a serious, lifelong autoimmune condition. There remains a significant unmet medical need for effective pharmacological treatments for CeD.

Methods: We utilized summary statistics for 2,888 druggable genes from the eQTLGen Consortium and the FinnGen Consortium for CeD. In our Mendelian Randomization (MR) analysis, we identified genes associated with CeD that had a false discovery rate (FDR) < 0.05 using the Inverse Variance Weighted (IVW) method. To enhance the reliability of the results, we validated them through colocalization analysis and Summary-data-based Mendelian Randomization (SMR) analyses.

Results: Through our analysis, we identified 18 druggable genes with a causal relationship to CeD under an FDR < 0.05. Subsequent colocalization and SMR analyses highlighted the PRKCD gene as a potential therapeutic target for CeD (IVW method: Odds Ratio 1.319, 95% Confidence Interval 1.182-1.471, P = 6.85E-07, FDR = 0.002). Additionally, these results have passed horizontal pleiotropy tests, heterogeneity analysis, and leave-one-out sensitivity analysis.

Discussion: The identification of PRKCD as a therapeutic target represents a significant advancement in addressing the unmet medical need for CeD treatment. However, the hypothesis that PRKCD contributes to CeD pathogenesis by regulating tight junction proteins and altering intestinal barrier function requires further experimental validation in future studies.

Conclusion: Our study is the first to identify the PRKCD gene as a potential therapeutic target for treating CeD, providing new insights into the treatment of CeD and guiding the development of corresponding therapeutic drugs.