Abstract
Observational studies suggest associations between elevated body mass index (BMI) and autoimmune liver diseases (AILDs), yet causal evidence remains limited. This Mendelian randomization (MR) study aimed to elucidate the causal role of BMI in AILDs and identify mediating pathways involving 91 circulating cytokines. Utilizing public genome-wide association study data, univariate and multivariate MR analyses were conducted to assess causal relationships between BMI and 3 AILDs. Mediation MR evaluated cytokine-mediated effects. Inverse variance weighted method served as the primary method, complemented by sensitivity analyses to address pleiotropy and heterogeneity. Genetically predicted higher BMI increased risks of autoimmune hepatitis (AIH; odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.07-1.93, P = .017) and primary biliary cholangitis (OR = 1.38, 95% CI = 1.14-1.67, P = .001), but inversely correlated with primary sclerosing cholangitis (PSC) risk (OR = 0.78, 95% CI = 0.62-0.98, P = .027). Multivariate MR confirmed BMI's independent effects after adjusting for alcohol and tobacco use. Mediation analysis indicated that tumor necrosis factor receptor superfamily (TNFRSF) member 9 could mediate the positive effects of higher BMI on AIH (OR = 1.02, 95% CI = 1.0005-1.07, 8.2%). Delta/Notch-like epidermal growth factor-related receptor (OR = 0.93, 95% CI = 0.87-0.98, 1.7%), interleukin [IL-8] (OR = 0.97, 95% CI = 0.92-0.99, 14.2%), and TNFRSF12 (OR = 0.95, 95% CI = 0.90-0.99, 18.7%) levels could mediate the negative effects of higher BMI on PSC. This study provided genetic evidence that higher BMI could increase the risk of AIH and primary biliary cholangitis and reduce the risk of PSC. Key circulating cytokines, such as TNFRSF 9, Delta/Notch-like epidermal growth factor-related receptor, TNFRSF12, and interleukin-8, could mediate the pathogenic pathways from BMI to AILDs. These findings highlight potential therapeutic targets and underscore the need for tailored prevention strategies in high-BMI populations.