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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: Genetically predicted rheumatoid arthritis (RA) (OR = 1.620, 95%CI 1.423-1.843, P = 2.506 × 10- 13) 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- 7) and RA (OR = 1.417, 95%CI 1.193-1.683, P = 7.193 × 10- 5) 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 D3 (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- 9), RA (OR = 1.543, 95%CI 1.279-1.861, P = 5.728 × 10- 6) and lower glycosylated hemoglobin (HbA1c) (OR = 0.268, 95%CI 0.141-0.510, P = 6.172 × 10- 5) were positively associated with an increased risk of PSC.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: Genetically predicted rheumatoid arthritis (RA) (OR = 1.620, 95%CI 1.423-1.843, P = 2.506 × 10- 13) 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- 7) and RA (OR = 1.417, 95%CI 1.193-1.683, P = 7.193 × 10- 5) 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 D3 (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- 9), RA (OR = 1.543, 95%CI 1.279-1.861, P = 5.728 × 10- 6) and lower glycosylated hemoglobin (HbA1c) (OR = 0.268, 95%CI 0.141-0.510, P = 6.172 × 10- 5) were positively associated with an increased risk of PSC.
CONCLUSIONS: 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.
摘要：
背景：自身免疫性肝病（AILD）的复杂病因涉及遗传，环境,以及其他尚未完全阐明的因素。本研究通过孟德尔随机化综合评估了遗传预测的可改变危险因素与AILD之间的因果关系。
方法：与29种暴露因子相关的遗传变异来自全基因组关联研究（GWAS）。与自身免疫性肝炎（AIH）的遗传关联数据，原发性胆汁性胆管炎(PBC)和原发性硬化性胆管炎(PSC)也可从公开的GWAS获得.进行单变量和多变量孟德尔随机化分析以确定AILD的潜在危险因素。
结果：遗传预测的类风湿性关节炎（RA）（OR=1.620，95CI1.423-1.843，P=2.506×10-13）与AIH风险增加显著相关。遗传预测吸烟开始（OR=1.637，95CI1.055-2.540，P=0.028），较低的咖啡摄入量（OR=0.359，95CI0.131-0.985，P=0.047），胆石症(OR=1.134,95CI1.023-1.257,P=0.017)和较高的C反应蛋白(CRP)(OR=1.397,95CI1.094-1.784,P=0.007)提示与AIH风险增加相关。遗传预测的炎症性肠病(IBD)(OR=1.212,95CI1.127~1.303,P=2.015×10-7)和RA(OR=1.417,95CI1.193~1.683,P=7.193×10-5)与PBC风险增加显著相关。遗传预测吸烟开始（OR=1.167，95CI1.005-1.355，P=0.043），系统性红斑狼疮（SLE）（OR=1.086，95CI1.017-1.160，P=0.014）和较高的CRP（OR=1.199，95CI1.019-1.410，P=0.028）与PBC风险增加相关。较高的维生素D3(OR=0.741,95CI0.560~0.980,P=0.036)和钙(OR=0.834,95CI0.699~0.995,P=0.044)水平是提示PBC的保护因素。遗传预测的吸烟开始（OR=0.630，95CI0.462-0.860，P=0.004）提示与PSC风险降低相关。遗传预测IBD（OR=1.252，95CI1.164-1.346，P=1.394×10-9），RA(OR=1.543,95CI1.279～1.861,P=5.728×10-6)和糖化血红蛋白(HbA1c)水平较低(OR=0.268,95CI0.141～0.510,P=6.172×10-5)与PSC风险增加呈正相关。
结论：关于29个基因预测的可改变的危险因素与AIH风险之间因果关系的证据，PBC,PSC是由这项研究提供的。这些发现为AILD的管理和预防策略提供了新的视角。
方法：与29种暴露因子相关的遗传变异来自全基因组关联研究（GWAS）。与自身免疫性肝炎（AIH）的遗传关联数据，原发性胆汁性胆管炎(PBC)和原发性硬化性胆管炎(PSC)也可从公开的GWAS获得.进行单变量和多变量孟德尔随机化分析以确定AILD的潜在危险因素。
结果：遗传预测的类风湿性关节炎（RA）（OR=1.620，95CI1.423-1.843，P=2.506×10-13）与AIH风险增加显著相关。遗传预测吸烟开始（OR=1.637，95CI1.055-2.540，P=0.028），较低的咖啡摄入量（OR=0.359，95CI0.131-0.985，P=0.047），胆石症(OR=1.134,95CI1.023-1.257,P=0.017)和较高的C反应蛋白(CRP)(OR=1.397,95CI1.094-1.784,P=0.007)提示与AIH风险增加相关。遗传预测的炎症性肠病(IBD)(OR=1.212,95CI1.127~1.303,P=2.015×10-7)和RA(OR=1.417,95CI1.193~1.683,P=7.193×10-5)与PBC风险增加显著相关。遗传预测吸烟开始（OR=1.167，95CI1.005-1.355，P=0.043），系统性红斑狼疮（SLE）（OR=1.086，95CI1.017-1.160，P=0.014）和较高的CRP（OR=1.199，95CI1.019-1.410，P=0.028）与PBC风险增加相关。较高的维生素D3(OR=0.741,95CI0.560~0.980,P=0.036)和钙(OR=0.834,95CI0.699~0.995,P=0.044)水平是提示PBC的保护因素。遗传预测的吸烟开始（OR=0.630，95CI0.462-0.860，P=0.004）提示与PSC风险降低相关。遗传预测IBD（OR=1.252，95CI1.164-1.346，P=1.394×10-9），RA(OR=1.543,95CI1.279～1.861,P=5.728×10-6)和糖化血红蛋白(HbA1c)水平较低(OR=0.268,95CI0.141～0.510,P=6.172×10-5)与PSC风险增加呈正相关。
结论：关于29个基因预测的可改变的危险因素与AIH风险之间因果关系的证据，PBC,PSC是由这项研究提供的。这些发现为AILD的管理和预防策略提供了新的视角。
