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.

Gao W ，Peng C ，Wang Z ，Li Y ，Liu M ... -  《Journal of Translational Medicine》

Association between autoimmune liver diseases and chronic hepatitis B: A multivariable Mendelian randomization study in European population.

Observational studies have indicated a link between autoimmune liver diseases (AILD) and chronic hepatitis B (CHB) through observational studies. The association between AILD and CHB remains indeterminate. A two-sample Mendelian randomization (MR) analysis was conducted to scrutinize the causal nexus between AILD and CHB utilizing summary statistics derived from extensive genome-wide association studies (GWASs) in European populations. The primary statistical methodology employed was the inverse variance-weighted (IVW) method to deduce the causal connection of AILD on CHB. This study incorporated primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) as subtypes of AILD. Additionally, we conducted a multivariable MR (MVMR) analysis to account for the potential confounding effects of smoking, alcohol consumption, body mass index (BMI), and some autoimmune diseases. Our MR investigation encompassed a cohort of 725,816 individuals. The MR analysis revealed that genetically predicted PSC significantly correlated with a reduced risk of CHB (IVW OR = 0.857; 95%CI: 0.770-0.953, P = 0.005). Conversely, the reverse MR analysis suggested that genetic susceptibility to PSC might not modify the risk of CHB (IVW OR = 1.004; 95% CI: 0.958-1.053, P = 0.866). Genetically proxied PBC and AIH exhibited no discernible causal association with CHB in the MR analysis using the IVW method (P = 0.583; P = 0.425). The MVMR analysis still indicated a decreased risk of CHB associated with PSC (OR = 0.853, P = 0.003). Our study elucidates a causal relationship between PSC and a diminished risk of CHB.

Zhang W ，Lang R 《-》

Causal effects of gut microbiome on autoimmune liver disease: a two-sample Mendelian randomization study.

Epidemiological studies have indicated a potential link between the gut microbiome and autoimmune liver disease (AILD) such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The relationship between the gut microbiome and autoimmune liver disease is still uncertain due to confounding variables. In our study, we aim to shed light on this relationship by employing a two-sample Mendelian randomization approach. We conducted a two-sample Mendelian randomization (MR) study using the R package "TwoSampleMR". The exposure data consisted of genetic variants associated with 194 bacterial traits obtained from the MiBioGen consortium. Summary statistics for AILD were obtained from the GWAS Catalog website. Furthermore, a series of sensitivity analyses were performed to validate the initial MR results. There were two, four and three bacteria traits associated with an increased risk of AIH. PBC, and PSC respectively. In contrast, there were five, two and five bacteria traits associated with a decreased risk for AIH, PBC and PSC. Notably, the genus_Clostridium_innocuum_group showed a negative association with AIH (OR = 0.67, 95% CI: 0.49-0.93), and the genus_Actinomyces was found to be genetically associated with a decreased risk of PSC (OR = 0.62, 95% CI: 0.42-0.90). Our study identified the causal impact of specific bacterial features on the risk of AILD subtypes. Particularly, the genus_Clostridium_innocuum_group and the genus_Actinomyces demonstrated significant protective effects against AIH and PSC respectively. These findings provide further support for the potential use of targeted probiotics in the management of AILD.

Fu Y ，Li J ，Zhu Y ，Chen C ，Liu J ，Gu S ，Zheng Y ，Li Y ... -  《BMC Medical Genomics》

Identifying the genetic association between systemic lupus erythematosus and the risk of autoimmune liver diseases.

Previous studies on the relationship between systemic lupus erythematosus (SLE) and autoimmune liver diseases (AILDs) are inconclusive. Therefore, we employed Mendelian randomization (MR) to explore the causal associations between SLE and AILDs. A two-sample MR analysis was performed using summary-level statistics sourced from genome-wide association study (GWAS) datasets. Inverse-variance weighting (IVW), MR‒Egger, and weighted median (WM) were further supported by several sensitivity analyses. We detected causal genetic associations between SLE and primary biliary cholangitis (PBC) (odds ratio (OR) = 1.31, 95% CI = 1.15-1.51, P < 0.01; adjusted OR = 1.63, 95% CI = 1.39-1.90, P < 0.01) and between SLE and primary sclerosing cholangitis (PSC) (OR = 1.09, 95% CI = 1.01-1.08, P = 0.03; adjusted OR = 1.10, 95% CI = 1.00-1.21, P = 0.04). No causal association was found between SLE and autoimmune hepatitis. We are the first to use MR analysis to explore the causal relationships between SLE and various AILDs, revealing an increased risk of PBC and PSC in individuals with SLE.

Huang W ，Jin T ，Zheng W ，Yin Q ，Yan Q ，Pan H ，Xu C ... -  《-》

Rosacea and autoimmune liver diseases: a two-sample Mendelian randomization study.

Rosacea and autoimmune liver diseases (AILDs) are diseases closely associated with immune system abnormalities. AILDs primarily includes autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). Currently, research on the association between these two conditions is limited. Therefore, this study employed the bidirectional Mendelian randomization (MR) method to investigate potential causal relationships between rosacea and AILDs based on genetic predictions. Summary data related to Rosacea, AIH, PSC, and PBC were obtained from public genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was used as the primary analytical approach, supplemented by the MR-Egger, weighted mode method, weighted median, and simple mode. A series of sensitivity analyses were also conducted to identify heterogeneity and pleiotropy effects. The MR analysis results indicated a significant increase in the risk of rosacea being associated with PBC (OR = 1.09, 95% CI = 1.02-1.18, P = 0.014), but no such association was found with AIH or PSC. Furthermore, this study did not find a significant impact of rosacea on the risk of AILDs. This study represents the first in-depth exploration of the potential causal relationship between rosacea and AILDs using MR analysis. Thes findings suggest an increased risk of rosacea among PBC patients.

Wu W ，Tong HM ，Li YS ，Cui J ... -  《-》