Inflammatory bowel disease and risk of autoimmune hepatitis: A univariable and multivariable Mendelian randomization study

Abstract

Objective: This study aimed to use Mendelian randomization (MR) to investigate the potential causal association between inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH).

Methods: Two-sample MR was performed to estimate the causal effect of IBD on AIH. The primary analysis employed the inverse variance weighted (IVW) method in univariable MR analysis, supplemented by additional methods including MR-Egger, weighted median, simple mode, and weighted mode. The p values were adjusted by FDR p-value adjustment. In the replication analysis, the primary IVW analysis was repeated and then pooled by meta-analysis. Sensitivity analyses were performed using Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out, and funnel plot analysis to evaluate the robustness of the MR findings. Additionally, multivariable MR (MVMR) was employed to estimate the direct causal effect of IBD on the risk of AIH.

Results: In univariable MR analysis, a significant positive causal association was observed between IBD (both Crohn's disease (CD) or ulcerative colitis (UC)) and the risk of AIH (for CD and AIH, the IVW odds ratio (OR) = 1.10, 95% confidence interval (CI) = 1.00-1.16, P = 0.045, FDR P = 0.045; for UC and AIH, the IVW OR = 1.07, 95% CI = 1.00-1.13, P = 0.038, FDR P = 0.076). Furthermore, no significant positive correlation between IBD and the risk of AIH (OR = 1.13, 95% CI = 0.94-1.35, P = 0.194). Sensitivity analysis revealed no pleiotropic bias. MVMR analysis further confirmed the direct causal effect of CD or UC on the risk of AIH after adjusting for the common risk factors (cigarettes per day and osteoporosis). In the replication analysis, the positive causal association between UC and the risk of AIH remain significant (the IVW odds ratio (OR) = 1.32, 95% CI = 1.18-1.48, P = 2.90E-06). While no significant positive association was observed between CD or IBD and the risk of AIH in the replication analysis, a suggestive positive association between the identified risk factors (UC, CD, and IBD) and the risk of AIH was detected in the meta-analysis (OR = 1.09, 95% CI = 1.05-1.13, P<0.0001).

Conclusion: This MR study revealed a positive impact of the identified risk factors (CD, UC and IBD) on the risk of AIH within the European population.

Fig 1. The study design overview and flowchart of MR analysis in this study.

GWAS, genome-wide association studies; SNP, single nucleotide polymorphisms; IVs, instrument variables; MR, Mendelian randomization; PRESSO, pleiotropy residual sum and outlier; IVW, inverse variance weighted; CD, Crohn’s diseaseor; UC, ulcerative colitis; IBD, inflammatory bowel disease.

Fig 2. Summary of univariate Mendelian randomization (MR) analyses of the causal effects between Crohn’s disease (CD) and the risk of autoimmune hepatitis (AIH).

OR, odds ratio; CI, confidence interval; FDR, false discovery rate.

Fig 3. Summary of multivariable Mendelian randomization (MR) analyses of the causal effects between Crohn’s disease (CD) or ulcerative colitis (UC) and the risk of autoimmune hepatitis (AIH) using inverse variance weighted (IVW) method.

OR, odds ratio; CI, confidence interval.

Fig 4. Summary of univariate Mendelian randomization (MR) analyses of the causal effects between ulcerative colitis (UC) and the risk of autoimmune hepatitis (AIH).

OR, odds ratio; CI, confidence interval; FDR, false discovery rate.

Fig 5. Summary of univariate Mendelian randomization (MR) analyses of the causal effects between inflammatory bowel disease (IBD) and the risk of autoimmune hepatitis (AIH).

OR, odds ratio; CI, confidence interval.

Fig 6. The effect of risk factors (Crohn’s disease (CD), ulcerative colitis (UC), and inflammatory bowel disease (IBD)) on the risk of autoimmune hepatitis (AIH) in replication analysis and meta-analysis.

OR, odds ratio; CI, confidence interval.