Exploring causality with biliary atresia at different levels: two-sample Mendelian randomization study.

Background: In recent years, Mendelian randomization (MR) has been widely used to infer causality of related disease risk exposures. However, this strategy has not been applied to biliary atresia (BA).

Methods: Genome-wide association studies (GWAS) data of 41 inflammatory cytokines, 731 immune cell traits, and 1400 metabolites were obtained from public databases as exposure factors. The outcome information was obtained from a GWAS meta-analysis of 499 children with BA and 1928 normal controls. Inverse variance weighting was the primary causality analysis. Cochran Q-test, MR-Egger intercept, MR pleiotropy residual sum and outlier, and 'leave-one-out' analyses were used for sensitivity analysis. Reverse MR, MR-Steiger, and Linkage Disequilibrium Score were used to exclude the effects of reverse causality, genetic association, and linkage disequilibrium.

Results: MR results showed that a total of seven traits had potential causal relationships with BA, including three inflammatory cytokines: eotaxin (odds ratio (OR)=1.45, 95% confidence interval (CI): 1.08 to 1.95, p _FDR=0.18), G-CSF (OR=4.21, 95% CI: 1.75 to 10.13, p _FDR=0.05) and MCP-1/MCAF (OR=1.53, 95% CI: 1.12 to 2.10, p _FDR=0.14); three immune cell traits: CD8dim NKT/T cells ratio (OR=0.59, 95% CI: 0.45 to 0.77, p _FDR=0.06), CD8dim NKT counts (OR=0.58, 95% CI: 0.43 to 0.78, p _FDR=0.06), CD8dim NKT/lymphocyte ratio (OR=0.63, 95% CI: 0.49 to 0.81, p _FDR=0.06); one metabolite: X-12261 levels (OR=2.86, 95% CI: 1.73 to 4.74, p _FDR=0.06).

Conclusions: In this study, eotaxin, G-CSF, MCP-1/MCAF, and X-12261 levels were shown to be risk factors for BA. However, CD8dim NKT/T cells ratio, CD8dim NKT counts, and CD8dim NKT/lymphocyte ratio were protective factors for BA. These findings provided a promising genetic basis for the etiology, diagnosis, and treatment of BA.