Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization.
Scientific reports
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.
10.1038/s41598-024-62509-x
Causal associations between systemic lupus erythematosus and primary biliary cholangitis: A bidirectional Mendelian randomization study.
Heliyon
Objectives:The association between systemic lupus erythematosus (SLE) and primary biliary cholangitis (PBC) has been increasingly recognized. However, the existence of causal connections between SLE and PBC has yet to be established. In this study, we aimed to investigate the bidirectional causation between SLE and PBC utilizing Mendelian randomization (MR) analysis. Methods:We acquired summary data from Genome-wide association studies (GWAS) for SLE and PBC from the IEU Open GWAS and FinnGen database. The inverse variance weighted (IVW) was employed as the key method to ascertain the causality between SLE and PBC. Subsequently, a range of sensitivity analyses were applied. We also performed a fixed-effects model meta-analysis to combine the MR results from different databases. Moreover, multivariable MR were conducted to clarify the roles of potential confounding factors. Results:Our univariable MR investigation provided compelling evidence supporting a causal relationship between SLE and PBC in both directions. Specifically, the IVW method demonstrated a strong casual effect of SLE on PBC (odds ratio (OR) = 1.17, 95 % confidence interval (CI) = 1.09-1.25, p < 0.001). In addition, the results of reverse MR analysis revealed that genetically predicted PBC was associated with an increased risk of SLE (OR = 1.39, 95 % CI = 1.32-1.45, p < 0.001). The sensitivity analyses indicated the absence of horizontal pleiotropy and heterogeneity. Furthermore, the causality between SLE and PBC remained significant even after adjusting for common risk factors in the multivariable MR analysis. Conclusions:Our study provides statistical evidence of a potential causal relationship between SLE and PBC, but further research is needed to the explore of the underlying mechanisms of these disorders.
10.1016/j.heliyon.2024.e34971
Genetic association and causal relationship between multiple modifiable risk factors and autoimmune liver disease: a two-sample mendelian randomization study.
Journal of translational medicine
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) was significantly associated with an increased risk of AIH. Genetically predicted smoking initiation (OR = 1.637, 95%CI 1.055-2.540, P = 0.028), lower coffee intake (OR = 0.359, 95%CI 0.131-0.985, P = 0.047), cholelithiasis (OR = 1.134, 95%CI 1.023-1.257, P = 0.017) and higher C-reactive protein (CRP) (OR = 1.397, 95%CI 1.094-1.784, P = 0.007) were suggestively associated with an increased risk of AIH. Genetically predicted inflammatory bowel disease (IBD) (OR = 1.212, 95%CI 1.127-1.303, P = 2.015 × 10) and RA (OR = 1.417, 95%CI 1.193-1.683, P = 7.193 × 10) were significantly associated with increased risk of PBC. Genetically predicted smoking initiation (OR = 1.167, 95%CI 1.005-1.355, P = 0.043), systemic lupus erythematosus (SLE) (OR = 1.086, 95%CI 1.017-1.160, P = 0.014) and higher CRP (OR = 1.199, 95%CI 1.019-1.410, P = 0.028) were suggestively associated with an increased risk of PBC. Higher vitamin D (OR = 0.741, 95%CI 0.560-0.980, P = 0.036) and calcium (OR = 0.834, 95%CI 0.699-0.995, P = 0.044) levels were suggestive protective factors for PBC. Genetically predicted smoking initiation (OR = 0.630, 95%CI 0.462-0.860, P = 0.004) was suggestively associated with a decreased risk of PSC. Genetically predicted IBD (OR = 1.252, 95%CI 1.164-1.346, P = 1.394 × 10), RA (OR = 1.543, 95%CI 1.279-1.861, P = 5.728 × 10) and lower glycosylated hemoglobin (HbA1c) (OR = 0.268, 95%CI 0.141-0.510, P = 6.172 × 10) were positively associated with an increased risk of PSC. 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.
10.1186/s12967-024-05247-y
Investigating the causal relationship and potential shared diagnostic genes between primary biliary cholangitis and systemic lupus erythematosus using bidirectional Mendelian randomization and transcriptomic analyses.
Frontiers in immunology
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.
10.3389/fimmu.2024.1270401
A Mendelian randomization study on the causal effects of cigarette smoking on liver fibrosis and cirrhosis.
Frontiers in medicine
Background:Liver fibrosis significantly impacts public health globally. Untreated liver fibrosis eventually results in cirrhosis. Cigarette smoking is the main etiologic factor for various diseases. However, the causal effects of cigarette smoking on liver fibrosis and cirrhosis have yet to be fully elucidated. Methods:In this study, Mendelian randomization (MR) analysis was performed to assess the association between cigarette smoking, liver fibrosis, and cirrhosis. Single-nucleotide polymorphisms (SNPs) were selected as instrumental variables from a genome-wide association study (GWAS) of European ancestry. Patients were divided into six exposure categories as follows: "ever smoked," "pack years of smoking," "age of smoking initiation," "smoking status: never," "smoking status: current," and "smoking status: previous." The outcomes of this study included liver fibrosis and cirrhosis. MR-Egger, weighted median, inverse variance weighted, simple mode, and weighted mode were selected as the analysis methods. Cochran's Q and the MR-PRESSO tests were conducted to measure heterogeneity. The MR-Egger method was performed to evaluate horizontal pleiotropy, while the "leave-one-out" analysis was performed for sensitivity testing. Results:The results of this study showed that having a smoking history increases the risk of liver fibrosis and cirrhosis ["ever smoked": odds ratio (OR) = 5.704, 95% CI: 1.166-27.910, = 0.032; "smoking status: previous": OR = 99.783, 95% CI: 2.969-3.353e+03, = 0.010]. A negative correlation was observed between patients who never smoked and liver fibrosis and cirrhosis ("smoking status: never": OR = 0.171, 95% CI: 0.041-0.719, = 0.016). However, there were no significant associations between "smoking status: current," "pack years of smoking," and "age of smoking initiation" and liver fibrosis and cirrhosis. Cigarette smoking did not have a significant horizontal pleiotropic effect on liver fibrosis and cirrhosis. The "Leave-one-out" sensitivity analysis indicated that the results were stable. Conclusion:The study confirmed the causal effects of cigarette smoking on liver fibrosis and cirrhosis.
10.3389/fmed.2024.1390049
Epidemiologic and genetic associations between primary biliary cholangitis and extrahepatic rheumatic diseases.
Journal of autoimmunity
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.
10.1016/j.jaut.2024.103289
Type 1 diabetes and combined acute and chronic complications are associated with risk of progression of liver fibrosis: a Mendelian randomization study.
Frontiers in endocrinology
Background:There has been controversy and uncertainty regarding the causal relationship between type 1 diabetes, its consequences, liver fibrosis, and cirrhosis. In order to determine the causal relationship, we conducted a Mendelian randomization study (MR). Methods:For the first time, we subjected multiple diabetes data to analyze its relationship with the progression of liver fibrosis. Once the instrumental variables had been extracted, we assessed them employing Cochran's Q multi-analysis, inverse variance weighted, MR-Egger, MR-PRESSO, weighted mode, and weighted median. Results:Genetically predicted type 1 diabetes (OR = 1.13, 95% CI: 1.04-1.23, = 3.42 × 10), type 1 diabetes without complications (OR = 1.12, 95% CI: 1.03-1.23, = 1.26 × 10), type 1 diabetes with coma (OR = 1.09, 95% CI: 1-1.18, = 4.74 × 10), type 1 diabetes with ketoacidosis (OR = 1.07, 95% CI: 1.01-1.13, = 1.3 × 10), type 1 diabetes with neurological complications (OR = 1.18, 95% CI: 1.11-1.26, = 4.05 × 10), type 1 diabetes with ophthalmic complications (OR = 1.16, 95% CI: 1.05-1.28, = 3.06 × 10), type 1 diabetes with renal complications (OR = 1.07, 95% CI: 1-1.13, * = 3.45 × 10), type 1 diabetes with other specified/multiple/unspecified complications (OR = 1.12, 95% CI: 1.02-1.23, = 1.41 × 10) were all associated with an increased risk of liver fibrosis progression. Conclusions:According to our MR investigation, type 1 diabetes and both its acute and chronic implications may increase the likelihood that liver fibrosis could continue to develop. Additionally, type 1 diabetes with neurological and ocular problems is more likely to accelerate the development of liver fibrosis and inflammation, which offers new insights for genetic investigations.
10.3389/fendo.2024.1302611
Primary biliary cholangitis has causal effects on systemic rheumatic diseases: a Mendelian randomization study.
Zhang Hai-Ping, Zhou Zhe, Chen Ke, Xiong Li-Fen, Wu Jun, Jin Lei
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.
10.1186/s12876-024-03319-3
Association of MCP-4, NRTN, and PD-L1 with the risk of hepatic fibrosis: A Mendelian randomization study.
Medicine
Previous studies have confirmed the affiliation between specific inflammatory cytokines and Hepatic fibrosis (HF); however, contradictions remain in the causality. The study implemented a bidirectional two-sample Mendelian randomization (MR) analysis with published statistics derived from Genome-wide Association Studies (GWAS) to investigate casualties between inflammatory cytokines and HF. Additionally, MR analysis was also introduced to consider if 1400 blood metabolites act as the key mediators in this process. Single nucleotide polymorphisms (SNPs) with strong correlations to inflammatory factors were selected for multiple MR analyses in this study. The inverse variance weighted method (IVW) was chosen as the principal analysis, and the others as the supportive. Besides, sensitivity tests were involved to identify potential heterogeneity and pleiotropic level. IVW methods revealed that a relatively high level of prediction-based monocyte chemoattractant protein-4 (MCP-4) (95% CI: 1.014-3.336, P = .045), along with neurturin (NRTN) (95% CI: 1.204-4.004, P = .010), may increase the risk of HF; while programmed cell death 1 ligand 1 (PD-L1) (95% CI: 0.223-0.928, P = .030), showed a protective effect on HF. No significant statistical differences were detected on any other inflammatory cytokines, nor did the impact of HF genetic predisposition on the 91 circulating inflammatory cytokines-related characteristics.
10.1097/MD.0000000000039655
The relationship between diverticular disease of intestine and cirrhosis: a two-sample mendelian randomization study.
Scientific reports
The correlation between diverticular disease of the intestine and cirrhosis is well-established, however, the presence of a genetic causal link between the two conditions remains uncertain. The study employed a two-sample Mendelian randomization approach utilizing the most recent genome-wide association study (GWAS) data to investigate the correlation between diverticulosis and liver cirrhosis. The primary analysis was conducted using the Inverse Variance Weighted (IVW) method, and was further corroborated by an array of statistical techniques including MR-Egger, Weighted Median, Weighted Mode, cML-MA, ConMix, MR-RAPS, and DIVW to ensure robustness and reliability of the findings.Heterogeneity was evaluated using Cochran's Q test, horizontal pleiotropy was assessed through MR-Egger regression, and leave-one-out analyses were performed to validate the causal relationships. The IVW method found that diverticular disease significantly reduces the risk of cirrhosis (OR = 0.849, 95% CI: 0.743-0.971, P = 0.016). All models had P-values < 0.05 and negative β values. MR-Egger regression showed no horizontal pleiotropy (P = 0.215), confirming SNP reliability. Cochran's Q values for IVW and MR-Egger were 57.23 (P = 0.39) and 55.62 (P = 0.41), indicating no heterogeneity. Sensitivity analysis with the leave-one-out method validated the robustness of the results. This research utilizes Mendelian randomization to illustrate the potential protective role of diverticulosis against liver cirrhosis. The results are analyzed through the lenses of gut microbiota and cytokine levels, providing new perspectives that may inform clinical approaches to diagnosis and treatment.
10.1038/s41598-024-74023-1
Causal impacts of educational attainment on chronic liver diseases and the mediating pathways: Mendelian randomization study.
Liver international : official journal of the International Association for the Study of the Liver
BACKGROUND AND AIMS:Educational attainment is an essential socio-economic indicator with broad implications for lifestyle behaviour and metabolic health. We aimed to investigate the causal effect of education on chronic liver diseases and the potential mediating pathways. METHODS:We applied univariable Mendelian randomization (MR) to assess the causal associations between educational attainment and non-alcoholic fatty liver disease (NAFLD) (cases/controls: 1578/307 576 in FinnGen; 1664/400 055 in UK Biobank), viral hepatitis (1772/307 382; 1215/403 316), hepatomegaly (199/222 728; 297/400 055), chronic hepatitis (699/301 014; 277/403 316), cirrhosis (1362/301 014; 114/400 055) and liver cancer (518/308 636; 344/393 372) using summary statistics of genome-wide association studies from the FinnGen Study and the UK Biobank, respectively. We used two-step MR to evaluate potential mediators and their mediation proportions in the association. RESULTS:Meta-analysis of inverse variance weighted MR estimates from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was causally associated with decreased risks of NAFLD (OR: 0.48; 95%CI: 0.37-0.62), viral hepatitis (0.54; 0.42-0.69) and chronic hepatitis (0.50; 0.32-0.79), but not hepatomegaly, cirrhosis and liver cancer. Nine, two and three out of 34 modifiable factors were identified as causal mediators in the associations of education with NAFLD, viral hepatitis and chronic hepatitis, respectively, including six adiposity traits (mediation proportion: 16.5%-32.0%), major depression (16.9%), two glucose metabolism-related traits (2.2%-15.8%) and two lipids (9.9%-12.1%). CONCLUSIONS:Our findings supported the causal protective effects of education on chronic liver diseases and outlined mediating pathways to inform prevention and intervention strategies to reduce the burden of liver diseases, especially for individuals with lower education.
10.1111/liv.15669
Associations of non-alcoholic fatty liver disease and cirrhosis with liver cancer in European and East Asian populations: A Mendelian randomization study.
Cancer reports (Hoboken, N.J.)
BACKGROUND:The positive relationships of non-alcoholic fatty liver disease (NAFLD) and cirrhosis with liver cancer were shown in previous observational studies, while further Mendelian randomization (MR) investigations are needed to confirm the possible causal associations. AIMS:This study aimed to explore whether NAFLD and cirrhosis were causally related to liver cancer using MR in European and East Asian populations. METHODS AND RESULTS:For European populations, NAFLD data were obtained from a genome-wide meta-analysis (8434 patients and 770 180 controls). The data on chronic elevation of alanine aminotransferase (cALT), a proxy of NAFLD, were derived from Million Veteran Program (68 725 patients and 95 472 controls). Cirrhosis data were collected from two sources: a genome-wide association study of five cohorts (4829 patients and 72 705 controls) and FinnGen (1931 patients and 216 861 controls). Liver cancer data were collected from FinnGen (304 patients and 174 006 controls). For East Asian populations, the data on cirrhosis (2184 patients and 210 269 controls) and hepatocellular carcinoma (1866 patients and 195 745 controls) were obtained from Biobank Japan. Three, 41, seven, six, and three single-nucleotide polymorphisms were used for NAFLD (European), cALT (European), cirrhosis (European-five cohorts), cirrhosis (European-FinnGen), and cirrhosis (East Asian), respectively. We used inverse-variance weighted as the primary method to calculate the odds ratio (OR) and 95% confidence interval (CI). Among European populations, genetically-predicted NAFLD, cALT, cirrhosis (five cohorts), and cirrhosis (FinnGen) were positively associated with liver cancer, with ORs (95% CIs) of 6.62 (3.81-11.50) (p < .001), 2.59 (1.70-3.94) (p < .001), 3.38 (2.41-4.75) (p < .001), and 2.62 (1.20-5.72) (p = .015). Among East Asian populations, there was also a positive association between genetically-predicted cirrhosis and hepatocellular carcinoma (OR = 2.12; 95% CI = 1.78-2.52; p < .001). CONCLUSION:This study utilized MR to complementarily confirm the positive connections of NAFLD and cirrhosis with liver cancer, as identified in earlier observational research. Subsequent MR investigations involving more liver cancer cases are needed.
10.1002/cnr2.1913
The causality between gut microbiome and liver cirrhosis: a bi-directional two-sample Mendelian randomization analysis.
Frontiers in microbiology
Background and aim:Previous studies have reported an association between gut microbiota and cirrhosis. However, the causality between intestinal flora and liver cirrhosis still remains unclear. In this study, bi-directional Mendelian randomization (MR) analysis was used to ascertain the potential causal effect between gut microbes and cirrhosis. Methods:Large-scale Genome Wide Association Study (GWAS) data of cirrhosis and gut microbes were obtained from FinnGen, Mibiogen consortium, and a GWAS meta-analysis of Alcoholic cirrhosis (ALC). Two-sample MR was performed to determine the causal relationship between gut microbiota and cirrhosis. Furthermore, a bi-directional MR analysis was employed to examine the direction of the causal relations. Result:In MR analysis, we found that 21 gut microbiotas were potentially associated with cirrhosis. In reverse MR analysis, 11 gut microbiotas displayed potentially associations between genetic liability in the gut microbiome and cirrhosis. We found that the family (OR: 1.59, 95% CI:1.10-2.29) might be harmful in cirrhotic conditions (ICD-10: K74). Furthermore, the genus might be a protective factor for cirrhosis (OR:0.55, 95% CI:0.34-0.88) and PBC (OR:0.68, 95% CI:0.52-0.89). Combining the results from the MR analysis and reverse MR analysis, we firstly identified the had a bi-directional causal effect on PBC (Forward: OR: 0.37, 95% CI:0.15-0.93; Reverse: OR: 1.03, 95% CI:1.00-1.05). Conclusion:We found a new potential causal effect between cirrhosis and intestinal flora and provided new insights into the role of gut microbiota in the pathological progression of liver cirrhosis.
10.3389/fmicb.2023.1256874
Genetic evidence of the causal relationship between chronic liver diseases and musculoskeletal disorders.
Journal of translational medicine
BACKGROUND:Chronic liver diseases constitute a major global public health burden, posing a substantial threat to patients' daily lives and even survival due to the potential development of musculoskeletal disorders. Although the relationship between chronic liver diseases and musculoskeletal disorders has received extensive attention, their causal relationship has not been comprehensively and systematically investigated. METHODS:This study aimed to assess the causal relationships between viral hepatitis, primary biliary cholangitis, primary sclerosing cholangitis (PSC), liver cirrhosis, and hepatocellular carcinoma (HCC) with osteoporosis, osteoarthritis, and sarcopenia through bidirectional Mendelian randomization (MR) research. The traits related to osteoporosis and osteoarthritis included both overall and site-specific phenotypes, and the traits linked to sarcopenia involved indicators of muscle mass and function. Random-effect inverse-variance weighted (IVW), weighted median, MR-Egger, and Causal Analysis Using the Summary Effect Estimates were used to evaluate causal effects, with IVW being the main analysis method. To enhance robustness, sensitivity analyses were performed using Cochran's Q test, MR-Egger intercept, MR-PRESSO global test, funnel plots, leave-one-out analyses, and latent causal variable model. RESULTS:The forward MR analysis indicated that PSC can reduce forearm bone mineral density (beta = - 0.0454, 95% CI - 0.0798 to - 0.0110; P = 0.0098) and increase the risk of overall osteoarthritis (OR = 1.012, 95% CI 1.002-1.022; P = 0.0247), while HCC can decrease grip strength (beta = - 0.0053, 95% CI - 0.008 to - 0.0025; P = 0.0002). The reverse MR analysis did not find significant causal effects of musculoskeletal disorders on chronic liver diseases. Additionally, no heterogeneity or pleiotropy was detected. CONCLUSIONS:These findings corroborate the causal effects of PSC on osteoporosis and osteoarthritis, as well as the causal impact of HCC on sarcopenia. Thus, the implementation of comprehensive preventive measures is imperative for PSC and HCC patients to mitigate the risk of musculoskeletal disorders, ultimately improving their quality of life.
10.1186/s12967-024-04941-1
Effect of viral hepatitis on type 2 diabetes: A Mendelian randomization study.
World journal of diabetes
BACKGROUND:The effects of viral hepatitis (VH) on type 2 diabetes (T2D) remain controversial. AIM:To analyze the causal correlation between different types of VH and T2D using Mendelian randomization (MR). METHODS:Single nucleotide polymorphisms of VH, chronic hepatitis B (CHB), chronic hepatitis C (CHC) and T2D were obtained from the BioBank Japan Project, European Bioinformatics Institute, and FinnGen. Inverse variance weighted, MR-Egger, and weighted median were used to test exposure-outcome associations. The MR-Egger intercept analysis and Cochran's test were used to assess horizontal pleiotropy and heterogeneity, respectively. Leave-one-out sensitivity analysis was used to evaluate the robustness of the MR analysis results. RESULTS:The MR analysis showed no significant causal relationship between VH and T2D in Europeans [odds ratio (OR) = 1.028; 95% confidence interval (CI): 0.995-1.062, = 0.101]. There was a negative causal association between CHB and T2D among East Asians (OR = 0.949; 95%CI: 0.931-0.968, < 0.001), while there was no significant causal association between CHC and T2D among East Asians (OR = 1.018; 95%CI: 0.959-1.081, = 0.551). Intercept analysis and Cochran's test showed no horizontal pleiotropy or heterogeneity ( > 0.05). Sensitivity analysis showed that the results were robust. CONCLUSION:Among East Asians, CHB is associated with a reduced T2D risk, but this association is limited by HBV load and cirrhosis. Although VH among Europeans and CHC among East Asians are not associated with the risk of T2D, focusing on blood glucose in patients with CHC is still relevant for the early detection of T2D induced by CHC-mediated pathways of hepatic steatosis, liver fibrosis, and cirrhosis.
10.4239/wjd.v15.i2.220
Osteoporosis and Primary Biliary Cholangitis: A Trans-ethnic Mendelian Randomization Analysis.
Clinical reviews in allergy & immunology
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). Our data supports a causal effect of PBC on osteoporosis, and the causality is independent of BMI, calcium, triglycerides, and several sex hormones.
10.1007/s12016-024-08986-4
Identifying the genetic association between systemic lupus erythematosus and the risk of autoimmune liver diseases.
Journal of autoimmunity
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.
10.1016/j.jaut.2024.103188