Bidirectional causal links between diabetes mellitus and autoimmune liver diseases: Insights from Mendelian randomization

Abstract

Background

Diabetes, a growing global public health issue, is often associated with autoimmune liver diseases (AILD), such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), in both type 1 diabetes (T1DM) and type 2 diabetes (T2DM). However, the causal relationship between these conditions remains unclear.

Methods

We used two-sample bidirectional Mendelian randomization (MR) to explore causal links between AILD and diabetes. Genetic variants identified from genome-wide association studies were used as instruments. Sensitivity and multivariable analyses adjusted for potential confounders were performed to assess the robustness of findings.

Results

Genetically predicted PBC (OR 1.41, 95% CI 1.19–1.67) and PSC (OR 1.39, 95% CI 1.14–1.68) were associated with an increased risk of T1DM. PBC (OR 1.03, 95% CI 1.01–1.05) was also linked to a higher risk of T2DM. In reverse MR analysis, genetically predicted T1DM was associated with an increased risk of PBC (OR 1.28, 95% CI 1.09–1.50), PSC (OR 1.27, 95% CI 1.14–1.41), and AIH (OR 1.13, 95% CI 1.06–1.19). Multivariable MR confirmed the causal effect of PBC and PSC on T1DM, but the link between PBC and T2DM weakened after adjusting for BMI and inflammatory bowel disease.

Conclusions

This study identifies bidirectional causal relationships between PBC/PSC and T1DM, suggesting shared pathogenesis, and T1DM also raises the risk for AIH. Although the link between PBC and T2DM weakened after adjusting for confounders, it highlights the complexity of genetic and environmental interactions, underscoring the importance of diabetes screening in AILD patients and guiding potential targeted therapies.