Genetic association and causal relationship between multiple modifiable risk factors and autoimmune liver disease: a two-sample mendelian randomization study

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^− 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.

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.