Department of Clinical Laboratory, Key Laboratory of Laboratory Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
J Transl Med. 2024 May 4;22(1):425. doi: 10.1186/s12967-024-05247-y.
The intricate etiology of autoimmune liver disease (AILD) involves genetic, environmental, and other factors that yet to be completely elucidated. This study comprehensively assessed the causal association between genetically predicted modifiable risk factors and AILD by employing Mendelian randomization.
Genetic variants associated with 29 exposure factors were obtained from genome-wide association studies (GWAS). Genetic association data with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) were also obtained from publicly available GWAS. Univariate and multivariate Mendelian randomization analyses were performed to identify potential risk factors for AILD.
Genetically predicted rheumatoid arthritis (RA) (OR = 1.620, 95%CI 1.423-1.843, P = 2.506 × 10) was significantly associated with an increased risk of AIH. Genetically predicted smoking initiation (OR = 1.637, 95%CI 1.055-2.540, P = 0.028), lower coffee intake (OR = 0.359, 95%CI 0.131-0.985, P = 0.047), cholelithiasis (OR = 1.134, 95%CI 1.023-1.257, P = 0.017) and higher C-reactive protein (CRP) (OR = 1.397, 95%CI 1.094-1.784, P = 0.007) were suggestively associated with an increased risk of AIH. Genetically predicted inflammatory bowel disease (IBD) (OR = 1.212, 95%CI 1.127-1.303, P = 2.015 × 10) and RA (OR = 1.417, 95%CI 1.193-1.683, P = 7.193 × 10) were significantly associated with increased risk of PBC. Genetically predicted smoking initiation (OR = 1.167, 95%CI 1.005-1.355, P = 0.043), systemic lupus erythematosus (SLE) (OR = 1.086, 95%CI 1.017-1.160, P = 0.014) and higher CRP (OR = 1.199, 95%CI 1.019-1.410, P = 0.028) were suggestively associated with an increased risk of PBC. Higher vitamin D (OR = 0.741, 95%CI 0.560-0.980, P = 0.036) and calcium (OR = 0.834, 95%CI 0.699-0.995, P = 0.044) levels were suggestive protective factors for PBC. Genetically predicted smoking initiation (OR = 0.630, 95%CI 0.462-0.860, P = 0.004) was suggestively associated with a decreased risk of PSC. Genetically predicted IBD (OR = 1.252, 95%CI 1.164-1.346, P = 1.394 × 10), RA (OR = 1.543, 95%CI 1.279-1.861, P = 5.728 × 10) and lower glycosylated hemoglobin (HbA1c) (OR = 0.268, 95%CI 0.141-0.510, P = 6.172 × 10) were positively associated with an increased risk of PSC.
Evidence on the causal relationship between 29 genetically predicted modifiable risk factors and the risk of AIH, PBC, and PSC is provided by this study. These findings provide fresh perspectives on the management and prevention strategies for AILD.
自身免疫性肝病（AILD）的复杂病因涉及遗传、环境和其他尚未完全阐明的因素。本研究通过孟德尔随机化全面评估了遗传可改变风险因素与 AILD 之间的因果关联。
从全基因组关联研究（GWAS）中获得与 29 种暴露因素相关的遗传变异。还从公开的 GWAS 中获得与自身免疫性肝炎（AIH）、原发性胆汁性胆管炎（PBC）和原发性硬化性胆管炎（PSC）相关的自身免疫性肝炎遗传关联数据。进行单变量和多变量孟德尔随机化分析，以确定 AILD 的潜在风险因素。
遗传预测的类风湿关节炎（RA）（OR=1.620，95%CI 1.423-1.843，P=2.506×10）与 AIH 的风险增加显著相关。遗传预测的吸烟起始（OR=1.637，95%CI 1.055-2.540，P=0.028）、咖啡摄入量较低（OR=0.359，95%CI 0.131-0.985，P=0.047）、胆石症（OR=1.134，95%CI 1.023-1.257，P=0.017）和 C 反应蛋白（CRP）水平较高（OR=1.397，95%CI 1.094-1.784，P=0.007）与 AIH 的风险增加呈提示性相关。遗传预测的炎症性肠病（IBD）（OR=1.212，95%CI 1.127-1.303，P=2.015×10）和 RA（OR=1.417，95%CI 1.193-1.683，P=7.193×10）与 PBC 的风险增加显著相关。遗传预测的吸烟起始（OR=1.167，95%CI 1.005-1.355，P=0.043）、系统性红斑狼疮（SLE）（OR=1.086，95%CI 1.017-1.160，P=0.014）和 CRP 水平较高（OR=1.199，95%CI 1.019-1.410，P=0.028）与 PBC 的风险增加呈提示性相关。较高的维生素 D（OR=0.741，95%CI 0.560-0.980，P=0.036）和钙（OR=0.834，95%CI 0.699-0.995，P=0.044）水平与 PBC 呈保护作用相关。遗传预测的吸烟起始（OR=0.630，95%CI 0.462-0.860，P=0.004）与 PSC 的风险降低呈提示性相关。遗传预测的 IBD（OR=1.252，95%CI 1.164-1.346，P=1.394×10）、RA（OR=1.543，95%CI 1.279-1.861，P=5.728×10）和较低的糖化血红蛋白（HbA1c）（OR=0.268，95%CI 0.141-0.510，P=6.172×10）与 PSC 的风险增加呈正相关。
本研究提供了 29 种遗传可改变风险因素与 AIH、PBC 和 PSC 风险之间因果关系的证据。这些发现为 AILD 的管理和预防策略提供了新的视角。
