Abstract
Purpose: The aim of this study is to utilize two-sample Mendelian randomization (MR) to investigate the potential causal relationship among psoriasis, iridocyclitis, and non-alcoholic fatty liver disease (NAFLD), and to explore any potential mediation effects. Methods: Pooled data were derived from the public genome-wide association study (GWAS) in NAFLD (finn-b-NAFLD), iridocyclitis (finn-b-H7_IRIDOCYCLITIS) and psoriasis (finn-b-L12_PSORI_VULG). Univariable MR (UVMR) analysis was implemented to explore the causal relationship among psoriasis, iridocyclitis, and NAFLD, and inverse variance weighting (IVW) was used as the primary analytical method. Additionally, Cochran's Q and MR-Egger tests were utilized to evaluate the heterogeneity and horizontal pleiotropy, respectively. Simultaneously, the reliability of MR results was evaluated by leave-one-out (LOO) method. Finally, multivariable MR (MVMR) analysis and mediation analysis were performed to further reveal the mechanism of mediation effect among the three diseases. Results: With regard to the results of IVW method, both iridocyclitis (P=0.0185, OR=1.0757) and psoriasis (P=0.0115, OR=1.1246) had significant causal relationships with the occurrence of NAFLD, and both were risk factors for NAFLD. Besides, it was observed that there was significant causal effect of iridocyclitis (P= 0.0181, OR=1.1729) on psoriasis and iridocyclitis was a risk factor. Additionally, there was a lack of heterogeneity (P>0.05) among the selected SNPs when MR analysis was conducted with NAFLD as the outcome. Horizontal pleiotropy was not detected by the MR-Egger test. The LOO analysis demonstrated that the instrumental variables were appropriately chosen, suggesting the reliability of the MR results. Ultimately, MVMR and mediation analysis revealed iridocyclitis affected the development of NAFLD, 20.81% of which was caused by the pathway of iridocyclitis induced psoriasis leading to NAFLD. Conclusion: This study highlighted that iridocyclitis was significantly associated with an increased risk of NAFLD and that psoriasis was involved in the mechanism by which iridocyclitis triggered NAFLD, which might offer potential preventive strategies for NAFLD.