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

Abstract

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, pFDR=0.18), G-CSF (OR=4.21, 95% CI: 1.75 to 10.13, pFDR=0.05) and MCP-1/MCAF (OR=1.53, 95% CI: 1.12 to 2.10, pFDR=0.14); three immune cell traits: CD8dim NKT/T cells ratio (OR=0.59, 95% CI: 0.45 to 0.77, pFDR=0.06), CD8dim NKT counts (OR=0.58, 95% CI: 0.43 to 0.78, pFDR=0.06), CD8dim NKT/lymphocyte ratio (OR=0.63, 95% CI: 0.49 to 0.81, pFDR=0.06); one metabolite: X-12261 levels (OR=2.86, 95% CI: 1.73 to 4.74, pFDR=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.