Lu Yechao, Sun Huiwen, Zhao Changdi, Zhao Shuaiyi, Zhou Ying, Zhang Guodong, Pan Xiaoping
The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.
College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
Medicine (Baltimore). 2025 Sep 5;104(36):e44194. doi: 10.1097/MD.0000000000044194.
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.
观察性研究表明，体重指数（BMI）升高与自身免疫性肝病（AILD）之间存在关联，但因果证据仍然有限。这项孟德尔随机化（MR）研究旨在阐明BMI在AILD中的因果作用，并确定涉及91种循环细胞因子的中介途径。利用公开的全基因组关联研究数据，进行了单变量和多变量MR分析，以评估BMI与3种AILD之间的因果关系。中介MR评估了细胞因子介导的效应。采用逆方差加权法作为主要方法，并辅以敏感性分析以解决多效性和异质性问题。基因预测的较高BMI增加了自身免疫性肝炎（AIH）的风险（优势比[OR]=1.43，95%置信区间[CI]=1.07-1.93，P=0.017）和原发性胆汁性胆管炎的风险（OR=1.38，95%CI=1.14-1.67，P=0.001），但与原发性硬化性胆管炎（PSC）风险呈负相关（OR=0.78，95%CI=0.62-0.98，P=0.027）。多变量MR在调整饮酒和吸烟因素后证实了BMI的独立作用。中介分析表明，肿瘤坏死因子受体超家族（TNFRSF）成员9可介导较高BMI对AIH的正向作用（OR=1.02，95%CI=1.0005-1.07，8.2%）。Delta/Notch样表皮生长因子相关受体（OR=0.93，95%CI=0.87-0.98，1.7%）、白细胞介素[IL-8]（OR=0.97，95%CI=0.92-0.99，14.2%）和TNFRSF12（OR=0.95，95%CI=0.90-0.99，18.7%）水平可介导较高BMI对PSC的负向作用。本研究提供了基因证据，表明较高的BMI可能增加AIH和原发性胆汁性胆管炎的风险，并降低PSC的风险。关键的循环细胞因子，如TNFRSF 9、Delta/Notch样表皮生长因子相关受体、TNFRSF12和白细胞介素-8，可介导从BMI到AILD的致病途径。这些发现突出了潜在的治疗靶点，并强调了在高BMI人群中制定针对性预防策略的必要性。
