Causal validation of immune antibody responses and nonalcoholic fatty liver disease: Evidence from Mendelian randomization and meta-analysis

In recent years, an increasing number of observational studies have reported the influence of immunity and antibodies on nonalcoholic fatty liver disease (NAFLD). However, no Mendelian randomization (MR) studies have yet been conducted to investigate the causal relationship in NAFLD. Based on a 2-sample MR framework, this study conducted MR analyses between 46 antibody immune response phenotypes and NAFLD using data from 2 different sources. Subsequently, the primary results from the inverse-variance weighted method were subjected to meta-analysis, and multiple testing correction was applied to the meta-analysis thresholds to ensure result accuracy. Finally, reverse MR analyses were performed to examine potential reverse causality between the antibody immune response phenotypes and NAFLD. MR analyses were conducted between 46 antibody immune response phenotypes and NAFLD using data from both the FinnGen R12 and the OpenGWAS databases. The inverse-variance weighted results from the 2 datasets were then combined through meta-analysis, and multiple testing correction was applied to the significance thresholds. The meta-analysis revealed an odds ratio of 1.06 (95% confidence interval: 1.02–1.11, P = .004). Moreover, the positive antibody immune response phenotype – Helicobacter pylori ( H pylori ) urease antibody levels – did not show evidence of reverse causality with NAFLD in either of the 2 datasets. The antibody immune response phenotype H pylori urease antibody levels is a risk factor for NAFLD, with the risk increase explicitly quantified as approximately 6% based on MR analysis.