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The study collected liver tissue samples from PBC patients and healthy controls and performed transcriptomic analysis of the cells in the samples using single-cell RNA sequencing. The expression characteristics of SHISA5 in PBC were revealed by comparing the difference of SHISA5 protein in the two groups of samples. The structure of SHISA5 protein was predicted and its possible biological function was analysed by bioinformatics method. The results showed that the expression of SHISA5 protein in liver tissue of PBC patients was significantly higher than that of healthy controls. Single-cell RNA sequencing data showed that SHISA5 was mainly expressed in hepatocytes and bile duct cells, and its expression level was positively correlated with the disease activity of PBC. Through structural prediction, we found that the SHISA5 protein molecule has a unique transmembrane domain and may be involved in cell signaling and intercellular interactions. Further functional analysis revealed that SHISA5 may participate in the pathological process of PBC by regulating the differentiation and function of bile duct cells., Competing Interests: Declaration of competing interest The authors declare no conflict of interest for this article., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background and Aim: The T cell receptor (TCR) can recognize a vast number of antigens and is closely associated with the pathogenesis of various diseases including autoimmune diseases and malignancies. However, the clinical significance of the TCR repertoire and its post-treatment changes remain unclear in liver diseases., Methods: We performed next-generation sequencing (NGS)-based TCR analysis using DNA obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors (HD, n = 5), primary biliary cholangitis (PBC, n = 5), autoimmune hepatitis (AIH, n = 5), and hepatocellular carcinoma (HCC, n = 5) and evaluated the changes after treatment., Results: Baseline TCR repertoire analysis demonstrated that TCR clonotype usage is restricted and diversity is low in all three disease groups (PBC, AIH, and HCC), particularly in PBC and AIH compared to HD (p < 0.05). Following treatment, clonotype usage and diversity did not change significantly, except in AIH, where diversity decreased further (p < 0.05 for clone Shannon diversity and clone evenness). Disease-specific usage of TCR beta genes and specific changes after therapy were observed in all groups. Analysis of clonotypes shared with other individuals (public clonotypes) revealed that nine public clonotypes in PBC, eight in AIH, and eight in HCC disappeared after treatment. Motif analysis identified one characteristic motif (NQPQH) in PBC., Conclusions: The diversity of the TCR repertoire, TCR beta chain usage, clonotypes, and motifs and their post-treatment changes are disease-specific in each liver disease, indicating that further TCR repertoire studies are needed to accelerate the understanding of liver disease pathogenesis from an immunological perspective., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The main goal of fine-mapping is the identification of relevant genetic variants that have a causal effect on some trait of interest, such as the presence of a disease. From a statistical point of view, fine mapping can be seen as a variable selection problem. Fine-mapping methods are often challenging to apply because of the presence of linkage disequilibrium (LD), that is, regions of the genome where the variants interrogated have high correlation. Several methods have been proposed to address this issue. Here we explore the 'Sum of Single Effects' (SuSiE) method, applied to real data (summary statistics) from a genome-wide meta-analysis of the autoimmune liver disease primary biliary cholangitis (PBC). Fine-mapping in this data set was previously performed using the FINEMAP program; we compare these previous results with those obtained from SuSiE, which provides an arguably more convenient and principled way of generating 'credible sets', that is set of predictors that are correlated with the response variable. This allows us to appropriately acknowledge the uncertainty when selecting the causal effects for the trait. We focus on the results from SuSiE-RSS, which fits the SuSiE model to summary statistics, such as z-scores, along with a correlation matrix. We also compare the SuSiE results to those obtained using a more recently developed method, h2-D2, which uses the same inputs. Overall, we find the results from SuSiE-RSS and, to a lesser extent, h2-D2, to be quite concordant with those previously obtained using FINEMAP. The resulting genes and biological pathways implicated are therefore also similar to those previously obtained, providing valuable confirmation of these previously reported results. Detailed examination of the credible sets identified suggests that, although for the majority of the loci (33 out of 56) the results from SuSiE-RSS seem most plausible, there are some loci (5 out of 56 loci) where the results from h2-D2 seem more compelling. Computer simulations suggest that, overall, SuSiE-RSS generally has slightly higher power, better precision, and better ability to identify the true number of causal variants in a region than h2-D2, although there are some scenarios where the power of h2-D2 is higher. Thus, in real data analysis, the use of complementary approaches such as both SuSiE and h2-D2 is potentially warranted., (© 2024 The Author(s). Genetic Epidemiology published by Wiley Periodicals LLC.)

Background: Prior observational research has shown relationships between immune cells, inflammatory proteins, and autoimmune liver diseases (AILD), but their causal associations remain controversial. Therefore, we aimed to clarify the causal association between them., Methods: We carried out a comprehensive Mendelian randomization (MR) analysis to clarify causal associations between 731 immune traits, 91 circulating inflammatory proteins, and AILD, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH). A two-step MR analysis was used to explore the mediating role of circulating inflammatory proteins. Additionally, we performed sensitivity analyses to evaluate the robustness of the results., Results: CD27 on IgD + CD24 + B cell, CD27 on IgD - CD38 dim B cell, CD27 on unswitched memory B cell, CD27 on switched memory B cell, and CD27 on CD24 + CD27 + B cell were risk factors for PBC. However, we detected protective effects of CD25 on IgD - CD27 - B cell against PBC and CD28 on resting CD4 + Treg cell against PSC. Circulating CD40, Interleukin-33, and Delta and Notch-like epidermal growth factor-related receptor were protective factors for PBC. Furthermore, CD40 mediated the association between immune traits and PBC, with the mediated proportions ranging from 18.3 % to 35.4 %. Tumor necrosis factor superfamily member 12 was identified as a risk factor for PSC, and monocyte chemotactic protein 3 was identified as a protective factor for PSC. Additionally, PBC and PSC had effects on eleven immune traits, which are suggested to be the consequences of them. We found no causal association between immune traits, circulating inflammatory proteins, and AIH. Sensitivity analyses demonstrated our results were robust., Conclusions: Our results demonstrate the causal roles of immune traits and inflammatory proteins in PBC and PSC, which reveals their pathogenesis. It is necessary to investigate the specific mechanism by which immune cells and inflammatory proteins affecting the occurrence of AILD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Primary biliary cholangitis (PBC) and gut microbiota (GM) are epidemiologically correlated but the causal inter-relationships remain poorly understood. We aim to explore the causal relationships between GM and PBC. Using the MiBioGen consortium, GWAS data for GM at the species level and the largest publicly available PBC GWAS data to date, we performed a bidirectional two-sample Mendelian randomization by the inverse variance weighted, MR-Egger, weighted median, weighted model and MR-PRESSO to elucidate the potential causal role of GM in PBC. To measure the heterogeneity of instrumental variables (IV), Cochran's Q statistic and MR-Egger intercept test were used. Genetically instrumented order Coriobacteriales (odds ratio [OR] = 2.18, 95% confidence interval [CI] 1.30-3.66, P = 0.004) significantly increased the risk for PBC, while genetically driven class Deltaproteobacteria (OR = 0.52, 95% CI 0.36-0.74, P = 0.002) causally decrease the NAFLD risk. Reverse MR analysis showed no significant association between PBC and the two specific GM. However, it indicated that PBC progression significantly increases the abundance of the class Bacteroidia, order Bacteroidales, and phylum Bacteroidetes (OR = 1.02, 95% CI 1.002-1.03, P = 0.026), while decreasing the abundance of the genus Lachnospiraceae UCG010 (OR = 0.98, 95% CI 0.96-0.995, P = 0.026). Our study demonstrated that genetically driven order Coriobacteriales and class Deltaproteobacteria were causally related to PBC risk. This causality provided a new perspective on ameliorating PBC by modulating GM. Our study demonstrated that genetically driven order Coriobacteriales and class Deltaproteobacteria were causally related to PBC risk. PBC was causally related to the abundance of four GM taxa(class Bacteroidia, order Bacteroidales, phylum Bacteroidetes and genus Lachnospiraceae UCG010). This causality provided a new perspective on ameliorating PBC by modulating GM., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background & Aims: Primary biliary cholangitis (PBC), a typical autoimmune liver disease, is characterized by an increased infiltration of immune cells. However, the specific molecular mechanisms regulating immune cell migration in PBC are unknown. Engulfment and cell motility 1 (ELMO1) plays an important function in cellular dynamics. In view of this, the aim of this study was to explore the expression of ELMO1 in PBC, its effects on the proliferation, migration, and secretion of inflammatory factors by the mainly regulated immune cells and the specific molecular mechanisms behind it., Methods: To determine the expression of ELMO1 in PBC and its major regulatory immune cells in PBC. The migratory and proliferative capacities of ELMO1-deficient macrophages were measured, and their pro-inflammatory cytokine secretion was also detected and explored mechanistically., Results: ELMO1 expression was up-regulated in the PBC patients and positively correlated with alkaline phosphatase (ALP). ELMO1 mainly regulated macrophages in the liver of PBC patients. Knockdown of ELMO1 did not affect macrophage proliferation, however,knockdown of ELMO1 significantly inhibited macrophage migration,downstream RAC1 activity was diminished, and reduced F-actin synthesis. Knockdown of ELMO1 reduced macrophage inflammatory factor secretion and NF-κB signaling pathway activity was decreased., Conclusions: ELMO1 regulates macrophage directed migration and attenuates inflammation via NF-κB signaling pathway in primary biliary cholangitis., Competing Interests: Conflict of Interest The authors have none to declare., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by multilineage immune dysregulation, which subsequently causes inflammation, fibrosis, and even cirrhosis of liver. Due to the limitation of traditional assays, the local hepatic immunopathogenesis of PBC has not been fully characterized. Here, we utilize single-cell RNA sequencing technology to depict the immune cell landscape and decipher the molecular mechanisms of PBC patients. We reveal that cholangiocytes and hepatic stellate cells are involved in liver inflammation and fibrosis. Moreover, Kupffer cells show increased levels of inflammatory factors and decreased scavenger function related genes, while T cells exhibit enhanced levels of inflammatory factors and reduced cytotoxicity related genes. Interestingly, we identify a liver-resident Th1-like population with JAK-STAT activation in the livers of both PBC patients and murine PBC model. Finally, blocking the JAK-STAT pathway alleviates the liver inflammation and eliminates the liver-resident Th1-like cells in the murine PBC model. In conclusion, our comprehensive single-cell transcriptome profiling expands the understanding of pathological mechanisms of PBC and provides potential targets for the treatment of PBC in patients., (© 2024. The Author(s).)

Background and Aims: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC., Approach and Results: Protein tyrosine phosphatase nonreceptor type 2 ( PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10 -8 ). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758., Conclusions: PTPN2 , a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Studies in epidemiology have indicated a link between chronic obstructive pulmonary disease (COPD) and various autoimmune conditions.This study aimed to investigate the potential causal link between nine autoimmune diseases with a genetic basis and COPD using a two-sample Mendelian randomization (MR) analysis., Method: To test the impact of susceptibility to immune-related outcomes on genetic prediction of COPD risk, we used pooled statistics from the largest genome-wide association study (GWAS) in Europe in a two-sample MR setting.Genetic data for type 1 diabetes, hypothyroidism, systemic lupus erythematosus, and primary biliary cirrhosis were obtained from the European Bioinformatics Institute (EBI), while data for multiple sclerosis and primary sclerosing cholangitis were extracted from the Integrative Epidemiology Unit (IEU) database. Additionally, genetic data for ulcerative colitis, rheumatoid arthritis, and celiac disease were also collected.These nine autoimmune diseases and the COPD cohort from the UK Biobank (1605 cases and 461,328 controls) were analyzed separately as exposure and outcome.Our primary method for the initial screening was inverse variance weighting (IVW).The MR-Egger regression test assessed multivariate validity, while the Cochran's Q test examined heterogeneity.To ensure the reliability of the findings, a leave-one-out analysis was conducted., Result: IVW discovered proof of type 1 diabetes (OR = 1.0003; 95 % CI = 1.0000-1.0005; P = 0.046), hypothyroidism (OR = 1.0004; 95 % CI = 1.0001-1.0008; P = 0.0263), celiac disease (OR = 1.0002; 95 % CI = 1.0000-1.0004; P = 0.0168) and systemic lupus erythematosus (OR = 1.0002; 95 % CI = 1.0000-1.0004; P = 0.049) were significantly linked to the heightened risk of COPD with no signs of variation or pleiotropy.Even after accounting for potential confounding factors like smoking, the correlation remained robust.Additionally, our research found that the IVW method did not indicate any causal link between COPD and multiple sclerosis, ulcerative colitis, rheumatoid arthritis, primary biliary cirrhosis, or primary sclerosing cholangitis (all P >0.05)., Conclusion: This research discovered that individuals with type 1 diabetes, hypothyroidism, celiac disease, and systemic lupus erythematosus have a higher likelihood of developing COPD.Additionally, this research revealed no connection between COPD and multiple sclerosis, ulcerative colitis, rheumatoid arthritis, primary biliary cirrhosis, or primary sclerosing cholangitis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Previous observational epidemiological studies have identified a potential association between inflammatory bowel disease (IBD) and sarcoidosis. Nonetheless, the precise biological mechanisms underlying this association remain unclear. Therefore, we adopted a Mendelian randomization (MR) approach to investigate the causal relationship between IBD with genetic susceptibility to sarcoidosis, as well as to explore the potential mediating role., Methods: The genetic associations were obtained from publicly available genome-wide association studies (GWASs) of European ancestry. The IBD dataset has 31,665 cases and 33,977 controls, consisting of 13,768 individuals with ulcerative colitis (UC) and 17,897 individuals with Crohn's disease (CD). The genetic associations of sarcoidosis with 4,854 cases and 446,523 controls. A bidirectional causality between IBD and sarcoidosis was implemented to be determined by a two-sample MR approach. The inverse variance weighted (IVW) method was utilized as the main statistical method, and a series of sensitivity analyses were performed to detect heterogeneity and horizontal pleiotropy. A two-step MR approach was used to investigate whether the mediating pathway from IBD to sarcoidosis was mediated by PBC., Results: The forward MR analysis indicated that genetic predisposition to IBD was significantly linked to an increased risk of sarcoidosis (OR = 1.088, 95% CI: 1.023-1.158, p IBD-sar = 7.498e-03). Similar causal associations were observed in CD (OR = 1.082, 95% CI: 1.028-1.138, p CD-sar = 2.397e-03) and UC (OR = 1.079, 95% CI: 1.006-1.158, p UC-sar = 0.034). Reverse MR analysis revealed that genetic susceptibility to sarcoidosis was correlated with an augmented risk of CD (OR = 1.306, 95% CI: 1.110-1.537, p sar-CD = 1.290e-03) but not IBD or UC. The mediation analysis via two-step MR showed that the causal influence of IBD and CD on sarcoidosis effects was partly mediated by PBC, and the mediating effect was 0.018 (95% CI: 0.005-0.031, p = 7.596e-03) with a mediated proportion of 21.397% in IBD, and 0.014 (95% CI: 0.004-0.024, p = 7.800e-03) with a mediated proportion of 17.737% in CD., Conclusions: The MR analysis provided evidence substantiating the causal effect of IBD (CD and UC) on an increased risk of sarcoidosis, with PBC playing a mediating role in IBD and CD. However, sarcoidosis only enhances the risk of developing CD, but not IBD or UC. These findings illuminate the etiology of sarcoidosis and contribute to the management of IBD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yi, Wu and He.)

Patients with primary biliary cholangitis (PBC) commonly experience extrahepatic rheumatic diseases. However, the epidemiologic and genetic associations as well as causal relationship between PBC and these extrahepatic conditions remain undetermined. In this study, we first conducted systematic review and meta-analyses by analyzing 73 studies comprising 334,963 participants across 17 countries and found strong phenotypic associations between PBC and rheumatic diseases. Next, we utilized large-scale genome-wide association study summary data to define the shared genetic architecture between PBC and rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Sjögren's syndrome (SS). We observed significant genetic correlations between PBC and each of the four rheumatic diseases. Pleiotropy and heritability enrichment analysis suggested the involvement of humoral immunity and interferon-associated processes for the comorbidity. Of note, we identified four variants shared between PBC and RA (rs80200208), SLE (rs9843053), and SSc (rs27524, rs3873182) using cross-trait meta-analysis. Additionally, several pleotropic loci for PBC and rheumatic diseases were found to share causal variants with gut microbes possessing immunoregulatory functions. Finally, Mendelian randomization revealed consistent evidence for a causal effect of PBC on RA, SLE, SSc, and SS, but no or inconsistent evidence for a causal effect of extrahepatic rheumatic diseases on PBC. Our study reveals a profound genetic overlap and causal relationships between PBC and extrahepatic rheumatic diseases, thus providing insights into shared biological mechanisms and novel therapeutic interventions., (Copyright © 2024. Published by Elsevier Ltd.)

Background & Aims: Gut dysbiosis and myeloid-derived suppressor cells (MDSCs) are implicated in primary biliary cholangitis (PBC) pathogenesis. However, it remains unknown whether gut microbiota or their metabolites can modulate MDSCs homeostasis to rectify immune dysregulation in PBC., Methods: We measured fecal short-chain fatty acids levels using targeted gas chromatography-mass spectrometry and analyzed circulating MDSCs using flow cytometry in 2 independent PBC cohorts. Human and murine MDSCs were differentiated in vitro in the presence of butyrate, followed by transcriptomic, epigenetic (CUT&Tag-seq and chromatin immunoprecipitation-quantitative polymerase chain reaction), and metabolic (untargeted liquid chromatography-mass spectrometry, mitochondrial stress test, and isotope tracing) analyses. The in vivo role of butyrate-MDSCs was evaluated in a 2-octynoic acid-bovine serum albumin-induced cholangitis murine model., Results: Decreased butyrate levels and defective MDSC function were found in patients with incomplete response to ursodeoxycholic acid, compared with those with adequate response. Butyrate induced expansion and suppressive activity of MDSCs in a manner dependent on PPARD-driven fatty acid β-oxidation (FAO). Pharmaceutical inhibition or genetic knockdown of the FAO rate-limiting gene CPT1A abolished the effect of butyrate. Furthermore, butyrate inhibited HDAC3 function, leading to enhanced acetylation of lysine 27 on histone H3 at promoter regions of PPARD and FAO genes in MDSCs. Therapeutically, butyrate administration alleviated immune-mediated cholangitis in mice via MDSCs, and adoptive transfer of butyrate-treated MDSCs also displayed protective efficacy. Importantly, reduced expression of FAO genes and impaired mitochondrial physiology were detected in MDSCs from ursodeoxycholic acid nonresponders, and their impaired suppressive function was restored by butyrate., Conclusions: We identify a critical role for butyrate in modulation of MDSC homeostasis by orchestrating epigenetic and metabolic crosstalk, proposing a novel therapeutic strategy for treating PBC., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: An association has been observed between primary biliary cholangitis (PBC) and systemic rheumatic diseases (SRDs) in observational studies, however the exact causal link remains unclear. We aimed to evaluate the causal effects of PBC on SRDs through Mendelian randomization (MR) analysis., Methods: The genome-wide association study (GWAS) summary data were obtained from MRC IEU OpenGWAS and FinnGen databases. Independent genetic variants for PBC were selected as instrumental variables. Inverse variance weighted was used as the main approach to evaluate the causal effects of PBC on Sjögren syndrome (SS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), mixed connective tissue disease (MCTD) and polymyositis (PM). Horizontal pleiotropy and heterogeneity were measured by MR‒Egger intercept test and Cochran's Q value, respectively., Results: PBC had causal effects on SS (OR = 1.177, P = 8.02e-09), RA (OR = 1.071, P = 9.80e-04), SLE (OR = 1.447, P = 1.04e-09), SSc (OR = 1.399, P = 2.52e-04), MCTD (OR = 1.306, P = 4.92e-14), and PM (OR = 1.416, P = 1.16e-04). Based on the MR‒Egger intercept tests, horizontal pleiotropy was absent (all P values > 0.05). The robustness of our results was further enhanced by the leave-one-out method., Conclusions: Our research has provided new insights into PBC and SRDs, indicating casual effects on various SRDs., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Background: Multiple factors are involved in the pathogenesis of primary biliary cholangitis (PBC), a chronic cholestatic liver disease, characterized by intrahepatic cholangiopathy. In particular, studies have suggested that environmental factors such as the presence of granulomas in the portal vein region are important for the development of PBC. This study aimed to comprehensively analyze and identify foreign-derived antigens in PBC liver tissue to confirm their involvement in PBC pathogenesis., Methods: Portal areas and hepatocyte regions were selectively dissected from formalin-fixed paraffin-embedded PBC liver tissue samples using the microlaser method, followed by total DNA extraction. We then validated whether the bacterial strains identified through 16S rRNA metagenomic analysis were detected in PBC liver tissues., Results: The most frequently detected bacterial genera in the PBC liver tissue samples were Sphingomonas panacis, Providencia, and Cutibacterium. These bacterial genera were also detected in the other PBC samples. Validation for the detection of S. panacis, the most abundant genus, revealed polymerase chain reaction bands extracted from the portal areas of all samples. They were also more highly expressed than bands detected in the hepatocyte region., Conclusion: S. panacis antigen was specifically detected in the portal areas of PBC liver tissues. The introduction of foreign-derived antigens into the liver as an environmental factor could be a possible mechanism for the development of PBC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Katsumi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Although numerous studies had revealed associations between autoimmune diseases (AIDs) and thyroid cancer (TC), the potential causal associations between the two remain poorly defined., Methods: Using five approaches, two-sample Mendelian randomization (MR) analyses were carried out to determine the causal effects of 12 major AIDs on risk of TC. The sensitivity analyses were conducted to verify the reliability of the analysis. The reverse MR analysis was performed to evaluate the possibility of reverse causation., Results: The results showed a significant causal association of systemic lupus erythematosus (SLE) and primary biliary cirrhosis (PBC) on the risk of TC. Genetically predicted PBC elevated the risk of TC (OR = 1.46, 95% CI = 1.06-2.02, p = 0.021). The risk of TC was also increased by genetically predicted SLE (OR = 6.52, 95% CI = 1.38-30.84, p = 0.018) with heterogeneity. After outlier-corrected analyses, the results still suggested that genetically predicted SLE increased the risk of TC ( p = 0.019). No evidence of a causal relationship between the remaining 10 AIDs and TC was observed. No reverse causal effects of TC on AIDs were found in reverse MR analysis., Conclusion: These findings support a significant causal association of SLE/PBC on the increased risk of TC, indicating that patients with SLE/PBC should be under a close monitoring of TC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Peng, Xu, Zhou, Du, Ge and Huang.)

Background & Aims: Primary biliary cholangitis (PBC) is a progressive-cholestatic autoimmune liver disease. Dendritic cells (DC) are professional antigen-presenting cells and their prominent presence around damaged bile ducts of PBC patients are documented. cDC1 is a rare subset of DC known for its cross-presentation abilities and interleukin 12 production. Our aim was to assess the role of cDC1 in the pathogenesis of PBC., Methods: We utilized an inducible murine model of PBC and took advantage of the DC reporter mice Zbtb46 gfp and the Batf3 -/- mice that specifically lack the cDC1 subset. cDC1 cells were sorted from blood of PBC patients and healthy individuals and subjected to Bulk-MARS-seq transcriptome analysis., Results: Histopathology assessment demonstrated peri-portal inflammation in wild type (WT) mice, whereas only minor abnormalities were observed in Batf3 -/- mice. Flow cytometry analysis revealed a two-fold reduction in hepatic CD8/CD4 T cells ratio in Batf3 -/- mice, suggesting reduced intrahepatic CD8 T cells expansion. Histological evidence of portal fibrosis was detected only in the WT but not in Batf3 -/- mice. This finding was supported by decreased expression levels of pro-fibrotic genes in the livers of Batf3 -/- mice. Transcriptome analysis of human cDC1, revealed 78 differentially expressed genes between PBC patients and controls. Genes related to antigen presentation, TNF and IFN signalling and mitochondrial dysfunction were significantly increased in cDC1 isolated from PBC patients., Conclusion: Our data illustrated the contribution the cDC1 subset in the pathogenesis of PBC and provides a novel direction for immune based cell-specific targeted therapeutic approach in PBC., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by elevated serum antimitochondrial antibody levels in 90-95 % of cases. However, the exact causal relationship between mitochondrial proteins and PBC remains unclear. This study aims to investigate and clarify this relationship., Methods: Genome-wide association data for mitochondrial proteins and PBC were obtained from public databases. The assessment of causal relationships between exposures and outcomes employed the Inverse Variance Weighted (IVW) method, MR Egger regression, and Weighted Median. Sensitivity analyses were systematically carried out to appraise the robustness of the Mendelian Randomization (MR) findings., Results: The analysis revealed two mitochondrial proteins exhibiting a causal relationship with PBC. Elevated SIRT5 levels demonstrated a positive correlation with an augmented susceptibility to PBC in the IVW approach (odds ratio, OR: 1.2907, 95 % CI: 1.062-1.568, p = 0.0102). Conversely, increased MRPL33 levels were associated with a decreased risk of PBC (OR: 0.8957, 95 % CI: 0.807-0.993, p = 0.0376). Sensitivity analysis corroborated these findings consistently., Conclusion: This investigation advances the notion of a potential causal association between elevated SIRT5 levels and an increased risk of PBC, alongside a decreased risk of PBC linked to elevated MRPL33 levels. The identified mitochondrial proteins may serve as viable biomarkers, offering pertinent insights for the understanding and addressing of PBC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background and Aims: Genetic variants influence primary biliary cholangitis (PBC) risk. We established and tested an accurate polygenic risk score (PRS) using these variants., Methods: Data from two Italian cohorts (OldIT 444 cases, 901 controls; NewIT 255 cases, 579 controls) were analysed. The latest international genome-wide meta-analysis provided effect size estimates. The PRS, together with human leukocyte antigen (HLA) status and sex, was included in an integrated risk model., Results: Starting from 46 non-HLA genes, 22 variants were selected. PBC patients in the OldIT cohort showed a higher risk score than controls: -.014 (interquartile range, IQR, -.023, .005) versus -.022 (IQR -.030, -.013) (p < 2.2 × 10 -16 ). For genetic-based prediction, the area under the curve (AUC) was .72; adding sex increased the AUC to .82. Validation in the NewIT cohort confirmed the model's accuracy (.71 without sex, .81 with sex). Individuals in the top group, representing the highest 25%, had a PBC risk approximately 14 times higher than that of the reference group (lowest 25%; p < 10 -6 )., Conclusion: The combination of sex and a novel PRS accurately discriminated between PBC cases and controls. The model identified a subset of individuals at increased risk of PBC who might benefit from tailored monitoring., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aims: Primary biliary cholangitis (PBC) is an autoimmune disease often accompanied by multisystem damage. This study aimed to explore the causal association between genetically predicted PBC and diabetes, as well as multiple cardiovascular diseases (CVDs)., Methods: Genome-wide association studies (GWAS) summary data of PBC in 24,510 individuals of European ancestry from the European Association for the Study of the Liver was used to identify genetically predicted PBC. We conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to estimate the impacts of PBC on diabetes (N = 17,685 to 318,014) and 20 CVDs from the genetic consortium (N = 171,875 to 1,030,836)., Results: SVMR provided evidence that genetically predicted PBC is associated with an increased risk of type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), heart failure (HF), hypertension, atrial fibrillation (AF), stroke, ischemic stroke, and small-vessel ischemic stroke. Additionally, there was no evidence of a causal association between PBC and coronary atherosclerosis. In the MVMR analysis, PBC maintained independent effects on T1D, HF, MI, and small-vessel ischemic stroke in most models., Conclusion: Our findings revealed the causal effects of PBC on diabetes and 7 CVDs, and no causal relationship was detected between PBC and coronary atherosclerosis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to this study., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: The epigenome, the set of modifications to DNA and associated molecules that control gene expression, cellular identity, and function, plays a major role in mediating cellular responses to outside factors. Thus, evaluation of the epigenetic state can provide insights into cellular adaptions occurring over the course of disease., Methods: We performed epigenome-wide association studies of primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) using the Illumina MethylationEPIC Bead Chip., Results: We found evidence of increased epigenetic age acceleration and differences in predicted immune cell composition in patients with PSC and PBC. Epigenetic profiles demonstrated differences in predicted protein levels including increased levels of tumor necrosis factor receptor superfamily member 1B in patients with cirrhotic compared to noncirrhotic PSC and PBC. Epigenome-wide association studies of PSC discovered strongly associated 5'-C-phosphate-G-3' sites in genes including vacuole membrane protein 1 and SOCS3, and epigenome-wide association studies of PBC found strong 5'-C-phosphate-G-3' associations in genes including NOD-like receptor family CARD domain containing 5, human leukocyte antigen-E, and PSMB8. Analyses identified disease-associated canonical pathways and upstream regulators involved with immune signaling and activation of macrophages and T-cells. A comparison of PSC and PBC data found relatively little overlap at the 5'-C-phosphate-G-3' and gene levels with slightly more overlap at the level of pathways and upstream regulators., Conclusions: This study provides insights into methylation profiles of patients that support current concepts of disease mechanisms and provide novel data to inspire future research. Studies to corroborate our findings and expand into other -omics layers will be invaluable to further our understanding of these rare diseases with the goal to improve and individualize prognosis and treatment., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: 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., Methods: 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., Results: 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)., Conclusion: Our study elucidates a causal relationship between PSC and a diminished risk of CHB., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune disorders characterized by progressive and chronic damage to the bile ducts, presenting clinicians with significant challenges. The objective of this study is to identify potential druggable targets to offer new avenues for treatment. A Mendelian randomization analysis was performed to identify druggable targets for PBC and PSC. This involved obtaining Cis-protein quantitative trait loci (Cis-pQTL) data from the deCODE database to serve as exposure. Outcome data for PBC (557 cases and 281,127 controls) and PSC (1,715 cases and 330,903 controls) were obtained from the FINNGEN database. Colocalization analysis was conducted to determine whether these features share the same associated SNPs. Validation of the expression level of druggable targets was done using the GSE119600 dataset and immunohistochemistry for clinical samples. Lastly, the DRUGBANK database was used to predict potential drugs. The MR analysis identified eight druggable targets each for PBC and PSC. Subsequent summary-data-based MR and colocalization analyses showed that LEFTY2 had strong evidence as a therapeutic candidate for PBC, while HSPB1 had moderate evidence. For PSC, only FCGR3B showed strong evidence as a therapeutic candidate. Additionally, upregulated expression of these genes was validated in PBC and PSC groups by GEO dataset and clinical samples. This study identifies two novel druggable targets with strong evidence for therapeutic candidates for PBC (LEFTY2 and HSPB1) and one for PSC (FCGR3B). These targets offer new therapeutic opportunities to address the challenging nature of PBC and PSC treatment.

An association has been observed between systemic lupus erythematosus (SLE) and primary biliary cholangitis (PBC) in observational studies, however, the exact causal link remains unclear. We aim to evaluate the causal relationships between SLE and PBC through bidirectional Mendelian randomization (MR). Single-nucleotide polymorphisms (SNPs) were selected as instrumental variables from publicly accessible genome-wide association studies (GWAS) in European populations. The PBC and SLE GWAS data were obtained from the MRC IEU Open GWAS database, consisting of 24,510 and 14,267 samples, respectively. After a series of quality control and outlier removal, inverse variance weighted was used as the primary approach to evaluate the causal association between SLE and PBC. The horizontal pleiotropy and heterogeneity were examined by the MR-Egger intercept test and Cochran Q value, respectively. Seven SNPs were included to examine the causal effect of SLE on PBC. Genetically predicted SLE may increase the risk of PBC development, with an odds ratio (OR) of 1.324 (95% confidence interval [CI] 1.220 ∼ 1.437, P ˂ .001). Twenty SNPs were included to explore the causal effect of PBC on SLE. Genetically predicted PBC may increase the risk of SLE development, with an OR of 1.414 (95% CI 1.323 ∼ 1.511, P ˂ .001). Horizontal pleiotropy and heterogeneity were absent (P > .05) among SNPs. The robustness of our results was further enhanced by using the leave-one-out method. Our research has provided new insights into SLE and PBC, indicating bidirectional causal associations between the 2 diseases. These findings offer valuable contributions to future clinical studies., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the causal relationship between PBC and EHAIDs is unclear. The genome-wide association analyses provided 14 GWAS data for PBC and EHAIDs, and bidirectional, two-sample MR analyses were performed to examine the relationship between PBC and EHAIDs. The analysis using MR provides a strong and meaningful estimation of the bidirectional correlation between PBC and 7 EHAIDs: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, autoimmune hypothyroidism, inflammatory bowel disease and ulcerative colitis of its types. In addition, PBC increases the risk of autoimmune thyroid diseases such as autoimmune hyperthyroidism and Graves' disease, as well as multiple sclerosis and psoriasis. Additionally, PBC is identified as a risk factor for Crohn's disease and Celiac disease. Based on genetic evidence, there may be connections between PBC and specific EHAIDs: not all coexisting EHAIDs induce PBC, and vice versa. This underscores the significance of prioritizing PBC in clinical practice. Additionally, if any liver function abnormalities are observed during treatment or with EHAIDs, it is crucial to consider the possibility of comorbid PBC., (© 2024. The Author(s).)

Background: Previous observational studies have demonstrated a link between diabetes mellitus(DM) and primary biliary cholangitis (PBC). Nevertheless, since these relationships might be confused, whether there is any causal connection or in which direction it exists is unclear. Our investigation aimed to identify the causal associations between DM and PBC., Methods: We acquired genome-wide association study (GWAS) datasets for PBC, Type 1 diabetes(T1DM), and Type 2 diabetes(T2DM) from published GWASs. Inverse variance-weighted (IVW), MR-Egger, weighted median (WM), Simple mode, and weighted mode methods were used to determine the causal relationships between DM(T1DM or T2DM) and PBC. Sensitivity analyses were also carried out to ensure the results were robust. To determine the causal relationship between PBC and DM(T1DM or T2DM), we also used reverse MR analysis., Results: T1DM was associated with a higher risk of PBC (OR 1.1525; 95% CI 1.0612-1.2517; p = 0.0007) in the IVW method, but no evidence of a causal effect T2DM on PBC was found (OR 0.9905; 95% CI 0.8446-1.1616; p = 0.9071) in IVW. Results of the reverse MR analysis suggested genetic susceptibility that PBC was associated with an increased risk of T1DM (IVW: OR 1.1991; 95% CI 1.12-1.2838; p = 1.81E-07), but no evidence of a causal effect PBC on T2DM was found (IVW: OR 1.0101; 95% CI 0.9892-1.0315; p = 0.3420)., Conclusion: The current study indicated that T1DM increased the risk of developing PBC and vice versa. There was no proof of a causal connection between PBC probability and T2DM. Our results require confirmation through additional replication in larger populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lv, Wang, Leng, Chen, Sun, Meng, Liu and Xiong.)

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 D 3 (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., (© 2024. The Author(s).)

Background: Observational studies have found an association between autoimmune liver disease (AILD) and Sjögren's syndrome (SS). However, the causal relationship between the two remains unknown. Clinical guidelines indicate that the coexistence of AILD with other autoimmune diseases may impact prognosis and quality of life; hence, early recognition and management of extrahepatic autoimmune diseases is particularly crucial. Against this backdrop, this study aimed to utilize Mendelian randomization (MR) methods to investigate the potential causal relationship between AILD and SS., Methods: We extracted summary statistics on AILD and SS from publicly available genome-wide association studies (GWAS) databases to identify appropriate instrumental variables (IVs). The inverse-variance weighted (IVW) method was utilized as the primary approach, with the weighted median (WM) method and MR-Egger method employed as supplementary methods to evaluate the potential causal relationship between the two conditions. Sensitivity analyses, including Cochran's Q test, MR-polynomial residuals and outliers (MR-PRESSO), MR-Egger intercept test, and the leave-one-out test, were performed to assess the stability of the results., Results: The MR study results indicate a significant causal relationship between PBC and PSC with the risk of SS in the European population (IVW: odds ratio [OR] = 1.155, 95% confidence interval [CI]: 1.092-1.222, p < .001; IVW: OR = 1.162, 95% CI: 1.051-1.284, p = .003). A series of sensitivity analyses have confirmed the reliability of the results., Conclusions: Our study indicates that the presence of both PBC and PSC increases the susceptibility to SS. However, no reliable causal relationship was found between SS and the risk of PBC or PSC. These findings contribute to elucidating the potential pathogenic mechanisms of the disease and are of significant importance for the management of patients with PBC and PSC., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: Observational studies have shown a higher prevalence of Sjogren's syndrome (SjS) in patients with primary biliary cholangitis (PBC) than in the healthy population, but whether this correlation is causal needs further confirmation. This study aimed to investigate the bidirectional causal relationship between PBC and SjS using Mendelian randomization (MR) analysis., Materials and Methods: We used pooled data from a large-scale genome-wide association study (GWAS) to select mutually independent genetic loci associated with PBC and SjS in people of European ancestry as instrumental variables (IVs). The causal association between PBC and SjS was analyzed by MR analysis using inverse variance weighting (IVW) and weighted median methods, and the ratio of ratios (OR) was used as an evaluation index. In addition, sensitivity analyses, including Cochran's Q test, MR-PRESSO, MR-Egger intercept test, and leave-one-out test, were performed to ensure the stability of the results., Results: A total of 20 validated IVs were selected for PBC, and the number of IVs for SjS was seven. Positive MR analysis showed that genetically predicted PBC was significantly associated with the risk of SjS (IVW OR=1.174, 95% CI: 1.107-1.246, p<0.001). The weighted median method further confirmed this result (OR=1.146, 95% CI: 1.053-1.247, p=0.016). Inverse MR analysis showed that genetic susceptibility to SjS also increased the risk of PBC (IVW OR=1.737, 95% CI: 1.280-2.357, p<0.001), and this result was also confirmed by the weighted median method (OR=1.398, 95% CI: 1.120-1.746, p=0.003)., Conclusions: Our study found that genetically predicted SjS increased the risk of PBC and vice versa in a European population. This may shed light on the etiology of PBC and the management of patients with SjS.

Background: 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., Methods: 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., Results: 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., Conclusions: 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., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aims: Aimed to identify a new susceptibility gene associated with primary biliary cholangitis (PBC) in Chinese Han and investigate the possible mechanism of that gene in PBC., Methods: A total of 466 PBC and 694 healthy controls (HC) were included in our study, and genotyping GTF2I gene variants by Sequenom. CD19 + B cells were isolated for Chromatin immunoprecipitation sequencing (ChIP-seq). Additionally, MEME-ChIP was utilized to perform searches for known motifs and de novo motif discovery. The GTF2I ChIP-seq of hematopoietic cell line (K562) results were obtained from ENCODE (GSE176987, GSE177691). The Genomic HyperBrowser was used to determine overlap and hierarchal clustering between ours and ENCODE datasets., Results: The frequency of the rs117026326 variant T allele was significantly higher in PBC patients than that in HC (20.26% compared with 13.89%, Pc = 1.09E-04). Furthermore, we observed an elevated proportion of GTF2I binding site located in the upstream and 5' UTR of genes in PBC in comparison with HC. Additionally, an in-depth analysis of IL21R region revealed that GTF2I might bind to the IL21R promoter to regulate the expression of the IL21R, with four peaks of GTF2I binding sites, including three increased binding sites in upstream, one increased binding site in 5' UTR. Motif analysis by MEME-ChIP uncovered five significant motifs. A significant overlap between our ChIP and GSE176987, GSE17769 were found by the Genomic HyperBroswer., Conclusions: Our study confirmed that GTF2I was associated with PBC in Chinese Han. Furthermore, our gene function analysis indicated that IL21R may be the target gene regulated by GTF2I., (© 2023. Asian Pacific Association for the Study of the Liver.)

Osteoporosis is a major clinical problem in many autoimmune diseases, including primary biliary cholangitis (PBC), the most common autoimmune liver disease. Osteoporosis is a major cause of fracture and related mortality. However, it remains unclear whether PBC confers a causally risk-increasing effect on osteoporosis. Herein, we aimed to investigate the causal relationship between PBC and osteoporosis and whether the relationship is independent of potential confounders. We performed bidirectional Mendelian randomization (MR) analyses to investigate the association between PBC (8021 cases and 16,489 controls) and osteoporosis in Europeans (the UK Biobank and FinnGen Consortium: 12,787 cases and 726,996 controls). The direct effect of PBC on osteoporosis was estimated using multivariable MR analyses. An independent replication was conducted in East Asians (PBC: 2495 cases and 4283 controls; osteoporosis: 9794 cases and 168,932 controls). Trans-ethnic meta-analysis was performed by pooling the MR estimates of Europeans and East Asians. Inverse-variance weighted analyses revealed that genetic liability to PBC was associated with a higher risk of osteoporosis in Europeans (OR, 1.040; 95% CI, 1.016-1.064; P = 0.001). Furthermore, the causal effect of PBC on osteoporosis persisted after adjusting for BMI, calcium, lipidemic traits, and sex hormones. The causal relationship was further validated in the East Asians (OR, 1.059; 95% CI, 1.023-1.096; P = 0.001). Trans-ethnic meta-analysis confirmed that PBC conferred increased risk on osteoporosis (OR, 1.045; 95% CI, 1.025-1.067; P = 8.17 × 10 -6 ). Our data supports a causal effect of PBC on osteoporosis, and the causality is independent of BMI, calcium, triglycerides, and several sex hormones., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) variant syndrome (VS) exhibit a complex overlap of AIH features with PBC, leading to poorer prognoses than those with PBC or AIH alone. The biomarkers associated with drug response and potential molecular mechanisms in this syndrome have not been fully elucidated., Methods: Whole-transcriptome sequencing was employed to discern differentially expressed (DE) RNAs within good responders (GR) and poor responders (PR) among patients with PBC/AIH VS. Subsequent gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted for the identified DE RNAs. Plasma metabolomics was employed to delineate the metabolic profiles distinguishing PR and GR groups. The quantification of immune cell profiles and associated cytokines was achieved through flow cytometry and immunoassay technology. Uni- and multivariable logistic regression analyses were conducted to construct a predictive model for insufficient biochemical response. The performance of the model was assessed by computing the area under the receiver operating characteristic (AUC) curve, sensitivity, and specificity., Findings: The analysis identified 224 differentially expressed (DE) mRNAs, 189 DE long non-coding RNAs, 39 DE circular RNAs, and 63 DE microRNAs. Functional pathway analysis revealed enrichment in lipid metabolic pathways and immune response. Metabolomics disclosed dysregulated lipid metabolism and identified PC (18:2/18:2) and PC (16:0/20:3) as predictors. CD4 + T helper (Th) cells, including Th2 cells and regulatory T cells (Tregs), were upregulated in the GR group. Pro-inflammatory cytokines (IFN-γ, TNF-α, IL-9, and IL-17) were downregulated in the GR group, while anti-inflammatory cytokines (IL-10, IL-4, IL-5, and IL-22) were elevated. Regulatory networks were constructed, identifying CACNA1H and ACAA1 as target genes. A predictive model based on these indicators demonstrated an AUC of 0.986 in the primary cohort and an AUC of 0.940 in the validation cohort for predicting complete biochemical response., Conclusion: A combined model integrating genomic, metabolic, and cytokinomic features demonstrated high accuracy in predicting insufficient biochemical response in patients with PBC/AIH VS. Early recognition of individuals at elevated risk for insufficient response allows for the prompt initiation of additional treatments., (© 2024. The Author(s).)

Background: The co-occurrence of primary biliary cholangitis (PBC) and systemic lupus erythematosus (SLE) has been consistently reported in observational studies. Nevertheless, the underlying causal correlation between these two conditions still needs to be established., Methods: We performed a bidirectional two-sample Mendelian randomization (MR) study to assess their causal association. Five MR analysis methods were utilized for causal inference, with inverse-variance weighted (IVW) selected as the primary method. The Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and the IVW Radial method were applied to exclude outlying SNPs. To assess the robustness of the MR results, five sensitivity analyses were carried out. Multivariable MR (MVMR) analysis was also employed to evaluate the effect of possible confounders. In addition, we integrated transcriptomic data from PBC and SLE, employing Weighted Gene Co-expression Network Analysis (WGCNA) to explore shared genes between the two diseases. Then, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment methods to perform on the shared genes. The Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithm was utilized to identify potential shared diagnostic genes. Finally, we verified the potential shared diagnostic genes in peripheral blood mononuclear cells (PBMCs)-specific cell populations of SLE patients by single-cell analysis., Results: Our MR study provided evidence that PBC had a causal relationship with SLE (IVW, OR: 1.347, 95% CI: 1.276 - 1.422, P < 0.001) after removing outliers (MR-PRESSO, rs35464393, rs3771317; IVW Radial, rs11065987, rs12924729, rs3745516). Conversely, SLE also had a causal association with PBC (IVW, OR: 1.225, 95% CI: 1.141 - 1.315, P < 0.001) after outlier correction (MR-PRESSO, rs11065987, rs3763295, rs7774434; IVW Radial, rs2297067). Sensitivity analyses confirmed the robustness of the MR findings. MVMR analysis indicated that body mass index (BMI), smoking and drinking were not confounding factors. Moreover, bioinformatic analysis identified PARP9, ABCA1, CEACAM1, and DDX60L as promising diagnostic biomarkers for PBC and SLE. These four genes are highly expressed in CD14+ monocytes in PBMCs of SLE patients and potentially associated with innate immune responses and immune activation., Conclusion: Our study confirmed the bidirectional causal relationship between PBC and SLE and identified PARP9, ABCA1, CEACAM1, and DDX60L genes as the most potentially shared diagnostic genes between the two diseases, providing insights for the exploration of the underlying mechanisms of these disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tao, Tang, Lv, Yuan, Wu, Zhao and Chen.)

Background: An association between primary biliary cholangitis (PBC) and connective tissue diseases (CTDs) [rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), systemic sclerosis (SSc)] has been found in observational studies. However, the direction causality is unclear. The aim of this study was to assess the causality between PBC and CTDs and to promote early screening, pre-emptive therapy, and accurate stratification., Methods: A two-sample Mendelian randomization (MR) analysis was performed to assess the causal relationship between PBC [Genome-Wide Association Study (GWAS) meta-analysis, 8021 cases/16498 controls], and SLE (GWAS meta-analysis, 8021 cases/16489 controls), RA(FinnGen, 6236 cases/14727 controls), SS(FinnGen, 2495 cases/365533 controls), SSc (FinnGen, 302 cases/213145 controls). Inverse variance weighting (IVW) was used as the primary analysis method, supplemented by four sensitivity analyses to assess the robustness of the results., Results: The IVW revealed that genetically predicted PBC increased the risk of SLE [odd's ratio (OR) = 1.43, 95% confidence interval (CI) 1.30-1.58, P < 0.001]), RA (OR = 1.09, 95%CI1.04-1.14, P<0.001), and SS (OR = 1.18, 95%CI1.12-1.24, P<0.001), but not that of SSc. In addition, no association was observed between CTDs as an exposure and PBC. Sensitivity analyses did not reveal horizontal pleiotropy., Conclusions: Our study provided new genetic evidence for a causal relationship between PBC and CTDs. PBC increased the risk of SLE, RA, and SS. Our findings highlighted the importance of active screening and intervention for CTDs in patients with PBC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Primary biliary cholangitis (PBC) is the most common of the autoimmune liver diseases, in which there is chronic small bile duct inflammation. The pathophysiology of PBC is multifactorial, involving immune dysregulation and damage to biliary epithelial cells, with influences from genetic factors, epigenetics, the gut-liver axis, and environmental exposures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Primary biliary cirrhosis (PBC) and psoriasis are frequently observed to co-occur in clinical settings. However, the causal associations and underlying mechanisms between PBC and psoriasis remain poorly defined., Methods: In this study, we conducted bidirectional MR analysis to explore the causal relationship between PBC and psoriasis using four MR methods: inverse-variance weighted, MR-Egger regression, weighted median, and weighted mode. Sensitivity analyses were carried out, employing different models and testing methods for comparison to assess the influence of heterogeneity and pleiotropy on our findings and to confirm the robustness of these results., Results: A causal relationship between the risk of PBC and psoriasis was identified, as confirmed by IVW analysis (OR: 1.081, 95%CI: 1.028~1.137, P <0.05). The other three MR methods also produced similar results. However, psoriasis did not have a causal effect on PBC risk (OR: 1.022, 95%CI: 0.935~1.118, P >0.05). The intercept of MR-Egger regression was 0.0013 ( P >0.05), indicating that genetic pleiotropy did not influence the results. Additionally, the leave-one-out analysis demonstrated the robustness of our MR findings., Conclusion: This study reveals a causal relationship between PBC and psoriasis, with PBC increasing the risk of psoriasis, but not the reverse. This potential causal relationship offers a new perspective on the etiology of PBC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Zhao, Xu, Zhang and Bai.)

Background: Primary biliary cholangitis (PBC) is a chronic immune-mediated liver disease. Previous genome-wide meta-analysis has identified the association between variants in TMEM163 with PBC. Here we aimed to evaluate the association between variants near the reported risk loci of TMEM163 at 2q21.3 and prognosis of PBC patients., Methods: We performed a retrospective analysis of 347 PBC patients treated with ursodeoxycholic acid (UDCA) for at least 1 year. We collected clinical data at diagnosis and 1 year after UDCA treatment. SNPs within 200 kb upstream and downstream of the lead variant were genotyped and screened., Results: We identified that rs661899 near MGAT5 and TMEM163 showed the strongest association with prognosis in PBC patients. Patients carrying the rs661899 T allele tended to respond incompletely to UDCA treatment and had worse performances in laboratory values including aspartate aminotransferase (53.5 vs 32 vs 28.5 U/L, p = 0.001), alkaline phosphate (157.25 vs 125 vs 113 U/L, p = 0.001), albumin (41.5 vs 42.3 vs 43.7 g/L, p = 0.008) and bilirubin (19.2 vs 14.9 vs 12.85 μmol/L, p = 0.001). GLOBE scores (p = 4.8 × 10 -5 ) and UK-PBC risk scores (p = 4.6 × 10 -4 ) were strongly correlated with rs661899 genotype. Patients with TT genotype had a higher risk for adverse events compared with CC genotype (p = 0.039) during the 1-year follow-up. Results were also verified in an independent cohort., Conclusions: PBC patients carrying the rs661899 T allele are associated with poor prognosis and adverse outcomes after 1-year UDCA therapy., (© 2023. Japanese Society of Gastroenterology.)

Background: Observational studies have identified a heightened risk of osteoporosis and fractures in patients with primary biliary cholangitis (PBC). However, conclusive evidence establishing a causal relationship between the two, and a clear mechanism explaining this association, remains elusive., Methods: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between PBC and osteoporosis. This analysis utilized five MR methods: inverse-variance weighted (IVW), MR-Egger, weighted median, weighted mode, and simple mode. Sensitivity analyses were performed, employing various models and testing methods, to assess the impact of heterogeneity and pleiotropy on the results and to confirm their robustness., Results: A causal relationship between PBC and osteoporosis risk was established through IVW analysis (OR: 1.049, 95%CI: 1.017-1.082, P =0.002). Three other MR analyses corroborated these findings. Conversely, osteoporosis was not found to causally affect PBC risk, as evidenced by IVW analysis (OR: 0.941, 95%CI: 0.783-1.129, P =0.511). Across all MR analyses, no heterogeneity or horizontal pleiotropy was detected among the instrumental variables (IVs). Furthermore, the leave-one-out analysis indicated that no single SNP disproportionately influenced the results, affirming the reliability of the bidirectional MR findings., Conclusion: This study establishes a positive causal relationship between PBC and the risk of osteoporosis, while no definitive causal link was found from osteoporosis to PBC. These findings offer new insights and guidance for managing bone health in PBC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Li, Bai, Teng, Yan and Han.)

Primary biliary cholangitis (PBC) is an autoimmune disorder characterized by intrahepatic bile duct destruction and cholestatic liver injury. Diagnosis of PBC is generally based on the existence of anti-mitochondrial antibody (AMA) in blood samples; however, some PBC patients are negative for serum AMA tests, and invasive liver histological testing is required in rare PBC cases. The current study seeks novel candidate genes that are associated with PBC status and have potentials for blood diagnostic testing. Human transcriptomic profiling data of liver and blood samples were obtained from Gene Expression Omnibus (GEO). Three GEO data series (GSE79850, GSE159676, and GSE119600) were downloaded, and bioinformatic analyses were performed. Various differentially expressed genes were identified in three data series by comparing PBC patients and control individuals. Twelve candidate genes were identified, which were upregulated in both liver tissues and blood samples of PBC patients in all three data series. The enrichment analysis demonstrated that 8 out of 12 candidate genes were associated with biological functions, which were closely related to autoimmune diseases including PBC. Candidate genes, especially ITGAL showed good potentials to distinguish PBC with other diseases. These candidate genes could be useful for diagnostic blood testing of PBC, although further clinical studies are required to evaluate their potentials as diagnostic biomarkers., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Pham et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The gut-liver axis indicates a close relationship between the gastrointestinal microbiome (GM) and primary biliary cholangitis (PBC). However, the causality of this relationship remains unknown. This study investigates the causal relationship between the GM and PBC using a bidirectional, two-sample Mendelian randomization (MR) analysis., Methods: Genome-wide association data for GM and PBC were obtained from public databases. The inverse-variance weighted method was the primary method used for MR analysis. Sensitivity analyses were conducted to assess the stability of the MR results. A reverse MR analysis was performed to investigate the possibility of reverse causality., Results: Three bacterial taxa were found to be causally related to PBC. Class Coriobacteriia (odds ratio (OR) = 2.18, 95% confidence interval (CI): 1.295-3.661, P< 0.05) and order Coriobacteriales (OR = 2.18, 95% CI: 1.295-3.661, P<0.05) were associated with a higher risk of PBC. Class Deltaproteobacteria (OR = 0.52, 95% CI: 0.362-0.742, P< 0.05) had a protective effect on PBC. There was no evidence of reverse causality between PBC and the identified bacterial taxa., Conclusion: Previously unrecognized taxa that may be involved in the pathogenesis of PBC were identified in this study, confirming the causality between the GM and PBC. These results provide novel microbial targets for the prevention and treatment of PBC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luo and You.)

Background: 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., Methods: 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., 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&#95;Clostridium&#95;innocuum&#95;group showed a negative association with AIH (OR = 0.67, 95% CI: 0.49-0.93), and the genus&#95;Actinomyces was found to be genetically associated with a decreased risk of PSC (OR = 0.62, 95% CI: 0.42-0.90)., Conclusions: Our study identified the causal impact of specific bacterial features on the risk of AILD subtypes. Particularly, the genus&#95;Clostridium&#95;innocuum&#95;group and the genus&#95;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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Primary biliary cholangitis (PBC) is an autoimmune liver disease, whose etiology is yet to be fully elucidated. Currently, ursodeoxycholic acid (UDCA) is the only first-line drug. However, 40% of PBC patients respond poorly to it and carry a potential risk of disease progression. So, in this study, we aimed to explore new biomarkers for risk stratification in PBC patients to enhance treatment., Methods: We first downloaded the clinical characteristics and microarray datasets of PBC patients from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified and subjected to enrichment analysis. Hub genes were further validated in multiple public datasets and PBC mouse model. Furthermore, we also verified the expression of the hub genes and developed a predictive model in our clinical specimens., Results: A total of 166 DEGs were identified in the GSE79850 dataset, including 95 upregulated and 71 downregulated genes. Enrichment analysis indicated that DEGs were significantly enriched in inflammatory or immune-related process. Among these DEGs, 15 risk-related genes were recognized and further validated in the GSE119600 cohort. Then, TXNIP, CD44, ENTPD1, and PDGFRB were identified as candidate hub genes. Finally, we proceeded to the next screening with these four genes in our serum samples and developed a three-gene panel. The gene panel could effectively identify those patients at risk of disease progression, yielding an AUC of 0.777 (95% CI, 0.657-0.870)., Conclusions: In summary, combining bioinformatics analysis and experiment validation, we identified TXNIP, CD44, and ENTPD1 as promising biomarkers for risk stratification in PBC patients., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The aim of the study was to present a woman affected of a narcolepsy with cataplexy (narcolepsy type 1) comorbid with an asymptomatic Primary Biliary Cholangitis (PBC). The HLA haplotype was DRB1*15:01, DQA1*01:02, DQB1*06:02. The allele DQB1*06:02 has been considered until now protective for PBC and dual pathology has not been published. We think the important clinical message of the Case would be of continuing to monitor adults with narcolepsy type 1 for late complications that may be associated with other autoimmune conditions. Clinicians should be aware of the relationship between Narcolepsy and PBC. This highlights the need for screening and management in these individuals., Competing Interests: Declaration of competing interest No declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Observational studies have indicated that the incidence of primary biliary cholangitis (PBC) is higher in inflammatory bowel disease (IBD) patients than that in healthy people. However, whether the correlation is causal remains unclear., Methods: The genetic associations with IBD were obtained from publicly available genome-wide association studies (GWAS) of European ancestry with 31 665 cases and 33 977 controls, consisting of 17 897 Crohn's disease (CD) and 13 768 ulcerative colitis (UC) cases. The genetic associations with PBC were obtained from a European GWAS with 2764 cases and 10 475 controls. A bidirectional two-sample Mendelian randomization (MR) design was implemented to determine the causal relationship between IBD and PBC. In the forward MR, the IBD was treated as the exposure while the PBC was the exposure in the reverse MR. The inverse-variance-weighted (IVW) method was utilized as the main statistic method, and a series of sensitivity analyses were performed to detect heterogeneity and horizontal pleiotropy., Results: A total of 99 valid instrumental variables (IVs) were selected for IBD and the number of IVs for PBC was 18. The forward MR analysis indicated that genetically predicted IBD (UC and CD) was significantly associated with an increased risk of PBC (IVW OR = 1.343; 95% CI: 1.220-1.466). Similar casual associations were observed in UC (IVW OR = 1.244; 95% CI: 1.057-1.430) and CD (IVW OR = 1.269; 95% CI: 1.159-1.379). Such results were still consistent in multiple MR methods. The reverse MR analysis implicated that genetic susceptibility to PBC might not alter the risk of IBD (IVW OR = 1.070; 95% CI: 0.984-1.164)., Conclusion: Our study found that genetically predicted IBD can increase the risk of PBC while not vice versa in the European population, which may enlighten the aetiology of PBC, together with the IBD patient management., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Primary biliary cholangitis (PBC) primarily affects female in their 4th to 6th decade of life at which stage female's sex hormones change dramatically. Sex hormones have a wide range of effects on the liver and immune system. However, it remains unclear whether sex hormonal changes mediate the onset of PBC., Aims: This study investigated the causal effect between total testosterone (TT), bioavailable testosterone (BAT), sex hormone binding globulin (SHBG) in female and PBC using public GWAS summary data., Methods: Data on TT, BAT, SHBG in female were obtained from a previous study based on the UK Biobank. PBC GWAS summary data was obtained from a genome-wide meta-analysis. We used several methods to make the conclusion robust. Various sensitivity analyses had been conducted to assess the consistency of our findings., Results: Our Mendelian randomization analysis revealed that the genetically predicted BAT in female was positively associated with PBC and SHBG in female was negatively associated with PBC. The results obtained from different methods are similar, which proves the reliability of the results., Conclusions: Our study supported a causal relationship of BAT and SHBG in female on PBC. To confirm the association between testosterone and PBC, more research should be conducted., Competing Interests: Conflict of interest None declared., (Copyright © 2023. Published by Elsevier Ltd.)

Inflammatory bowel disease (IBD) has been reported to be associated with hepatobiliary diseases. Previous observational and Mendelian randomization (MR) studies have suggested a causal association between IBD and primary sclerosing cholangitis (PSC). However, it is unclear whether IBD has a causal association with primary biliary cholangitis (PBC): another autoimmune liver disease. We obtained genome-wide association study (GWAS) statistics from published GWASs for PBC, UC, and CD. We screened qualified instrumental variables (IVs) based on the three major assumptions of MR. To determine the causal relationships between UC or CD and PBC, two-sample MR analyses were performed using inverse variance-weighted (IVW), MR-Egger, and weighted median (WM) methods, and sensitivity analyses were conducted to validate the robustness of the results. We also conducted reverse MR analysis to reveal the causal association between PBC and UC or CD. UC was associated with a higher risk of PBC (OR 1.35, 95% CI 1.05-1.73, P = 0.02) in the IVW method, and CD was associated with an increased risk of PBC (OR 1.18, 95% CI 1.03-1.36, P = 0.02) in IVW. The weighted median and MR-Egger regression of both diseases showed a consistent direction but were not statistically significant. Results of the reverse MR analysis did not suggest genetic susceptibility that PBC was associated with an increased risk of UC (OR 1.05, 95% CI 0.95-1.17, P = 0.34) or CD (OR 1.1, 95% CI 0.99-1.20, P = 0.06). The present study revealed that IBD subtypes could increase the incidence of PBC, but in turn, PBC did not increase the incidence of IBD subtypes. Understanding that IBD and PBC constitute mutual risk factors can help with the clinical management of both diseases., (© 2023. The Author(s).)