Risk Of Primary Biliary Cholangitis Research Articles

Pretransplant Evaluation and Liver Transplantation Outcome in PBC Patients.

Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic liver disease characterized by progressive cholangiocyte and bile duct destruction leading to fibrosis and finally to liver cirrhosis. The presence of disease-specific serological antimitochondrial antibody (AMA) together with elevated alkaline phosphatase (ALP) as a biomarker of cholestasis is sufficient for diagnosis. Ursodeoxycholic acid (UDCA) is the first treatment option for PBC. Up to 40% of patients have an incomplete response to therapy, and over time disease progresses to liver cirrhosis. Several risk scores are proposed for better evaluation of patients before and during treatment to stratify patients at increased risk of disease progression. GLOBE score and UK PBC risk score are used for the evaluation of UDCA treatment and Mayo risk score for transplant-free survival. Liver transplantation (LT) is the only treatment option for end-stage liver disease. More than 10 years after LT, 40% of patients experience recurrence of the disease. A liver biopsy is required to establish rPBC (recurrent primary biliary cholangitis). The only treatment option for rPBC is UDCA, and data show biochemical and clinical improvement, plus potential beneficial effects for use after transplantation for the prevention of rPBC development. Additional studies are required to assess the full impact of rPBC on graft and recipient survival and for treatment options for rPBC.

Evaluation of Inhibitory Antibodies against the Muscarinic Acetylcholine Receptor Type 3 in Patients with Primary Biliary Cholangitis and Primary Sclerosing Cholangitis.

Background: Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) constitute rare chronic inflammatory biliary diseases which likely comprise genetic, environmental and autoimmune factors. Specific inhibitory (auto-) antibodies against the muscarinic acetylcholine receptor type 3 (mAChR3 auto-ab) may contribute to the pathogenesis of chronic biliary inflammation by modulating mAChR3− mediated signaling. Aims: The aim of this study was to analyze the prevalence and relevance of inhibitory mAChR3 auto-ab (mAChR3inh+ auto-ab) in a large cohort of PBC patients from two independent tertiary centers in Berlin and Leipzig in comparison to a large PSC cohort. Baseline parameters and response rates to standard treatment with ursodeoxycholic acid (UDCA) were characterized with respect to the individual mAChR3 auto-ab status. Methods: In total, the study population comprised 437 PBC patients, 187 PSC patients and 80 healthy controls. Clinical and laboratory baseline characteristics were retrieved from medical records. The response to ursodeoxycholic acid (UDCA) therapy after 12 months of treatment was available in 176 PBC and 45 PSC patients. Results: The prevalence of mAChR3inh+ auto-ab was significantly higher among PBC patients (11.2%, 49/437; p = 0.008 vs. healthy controls) and PSC patients (33.6%, 63/187; p < 0.0001 vs. healthy controls) compared to healthy controls (2.5%, 2/80), respectively. PBC patients with mAChR3inh+ auto-ab exhibited significantly higher levels of alkaline phosphatase (ALP) and bilirubin, which constitute established parameters for PBC risk stratification. Moreover, mAChR3inh+ PBC patients tended to show decreased response rates to UDCA therapy compared to PBC patients without mAChR3inh+ auto-ab (mAChR3− PBC). In contrast, PSC patients with mAChR3inh+ auto-ab showed no significant differences in laboratory findings compared to mAChR3 auto-ab negative (mAChR3−) PSC patients. Conclusion: MAChR3inh+ auto-ab might be involved in the pathogenesis and treatment response of chronic biliary inflammation in patients with PBC but not in patients with PSC.

101Pre-onset sun exposure significantly associated with risk of primary biliary cirrhosis

Abstract Background Primary biliary cholangitis (PBC) is an autoimmune destructive condition of the gall bladder, with environmental factors like sun exposure implicated in its aetiology, similar to multiple sclerosis. Using a case-control study design, we assessed sun exposure across the life course prior to PBC diagnosis between PBC cases and age/sex-matched healthy controls. Methods Cases with definite/probable PBC were recruited, these having been identified from a PBC prevalence study. Age/sex matched controls were recruited from the electoral roll or at the Austin Hospital. Pre-onset sun exposure behaviours were queried at baseline by questionnaire and life calendar, this combined with ambient UVR data to estimate total UVR load. Relationships with case status were assessed using conditional logistic regression. Results 200 cases and 200 age/sex-matched controls were recruited. 91% of the cases were female and the mean age was 63.6 years. Increasing sun exposure was associated with significantly lower odds of being a case, robust to adjustment for birthplace, education and smoking, the strongest associations seen for summer exposure in 6-10yo (OR = 0.39), 11-16yo (OR = 0.44), and 16-20yo (OR = 0.47). Similar results were seen for ambient UVR. Conclusions Higher pre-onset sun exposure and UVR load were associated with a decreased risk of primary biliary cholangitis. This is the first study that has examined the environmental risk factors of sun exposure and UV radiation with regard to PBC. Key messages In line with the observation of a significant latitudinal gradient in PBC prevalence, this work shows that pre-onset sun exposure is significantly lower among PBC cases compared to matched controls, suggesting sun exposure has an aetiological relationship with PBC risk.

Comparative characteristics of the clinical and laboratory features of the primary Sjogren’s syndrome associated with anticentromere antibodies and the “classic” subtype of the disease

Objective: to compare clinical and laboratory manifestations in 2 groups of patients with primary Sjogren’s syndrome (pSS): with and without anticentromere antibodies (ACA); compare the incidence, clinical and laboratory characteristics of lymphomas in these two groups.Materials and methods. We examined 119 patients with ACA-positive pSS (pSS-ACA+). pSS was diagnosed based on Russian 2001 criteria, systemic sclerosis (SSc) – criteria ACR/EULAR 2013. To diagnose liver diseases, the level of transaminases, alkaline phosphatase and antimitochondrial antibodies (AMA) was determined, as well as liver biopsy. The diagnosis of primary biliary cholangitis (PBC) was established according to the recommendations of the American Association for the Study of Liver Diseases, the Russian Gastroenterological Association and the Russian Society for the Study of the Liver. Lymphomas were diagnosed according to histological, immunohistochemical and molecular studies of affected organs biopsies, according to the classification of the World Health Organization. A combination of pSS and SSc was diagnosed in 37 patients, and they were excluded from further analysis. We compared clinical and laboratory features in patients with pSS-ACA+ (n=82) and ACA-negative pSS (pSS-ACA–, n=64) and characterized lymphomas in the pSS-ACA+ (n = 14) and pSS-ACA– (n=10) groups.Results and discussion. In patients with pSS-ACA+, a later age of disease onset was revealed, the duration of the disease before lymphoma development did not differ. In patients with pSS-ACA+, we found a lower frequency of rheumatoid factor (RF), antibodies to Ro (anti-Ro) and La (anti-La), decreased C3-complement, hypergammaglobulinemia, increased IgG concentration, CRP, increased ESR, leukopenia and anemia. 51.2% of patients with pSS-ACA+ were seronegative for anti-Ro, anti-La and RF. Patients with pSS-ACA+ had a higher frequency of AMA and elevated IgM. The incidence of cryoglobulinemia and paraproteinemia did not differ. The frequency of recurrent parotitis in pSS-ACA+ was significantly lower, there were no differences in the frequency and severity of other signs of salivary and lacrimal gland damage. PBC and epitheliitis of the biliary ducts in patients with pSS-ACA+ were detected significantly more often. Damage to the peripheral nervous system, lungs, hypergammaglobulinemic purpura, arthralgia and autoimmune thyroiditis were significantly more often detected in the group of patients with pSS-ACA–. In the pSS-ACA+ group, Raynaud’s phenomenon was significantly more frequent, mainly with scleroderma-type capillaroscopic abnormalities. There was no difference in the frequency of other signs characteristic of SSc. MALT lymphomas were diagnosed in the study groups with the same frequency. Patients with lymphomas in the pSS-ACA+ group were characterized by significantly higher laboratory activity. All patients with lymphomas in both groups showed persistent parotid salivary gland enlargement. Lymphomas in both groups developed in patients with late stage salivary and lacrimal gland damage, systemic manifestations of pSS in both groups were rare.Conclusion. pSS-ACA+ is an independent subtype of pSS, which has a number of significant clinical and laboratory differences from the “classic” variant of the disease. ACA in pSS are associated with a low frequency of anti-Ro, anti-La, and RF, as well as an increased risk of PBC and limited SSc. MALT lymphomas in the pSS-ACA+ and pSS-ACA– groups developed with the same frequency and were associated with the progression of glandular damage, regardless of the presence of systemic manifestations.

Detection of anti-mitochondrial 2-oxoacid dehydrogenase complex subunit's antibodies for the diagnosis of Primary Biliary Cholangitis

Anti-mitochondrial antibodies (AMA), directed against the E2 subunits of the 2-oxo acid dehydrogenase complexes, are markers of Primary Biliary Cholangitis (PBC), a chronic autoimmune liver disease. However, it has not been stablished the clinical significance of subunits-specific AMA type PDC-E2 subunit of the pyruvate dehydrogenase complex-, BCOADC-E2 subunit of the branched-chain 2-oxo acid dehydrogenase complex-, OGDC-E2 subunit of the 2-oxo-glutarate dehydrogenase complex- and nPDC -native pyruvate dehydrogenase complex (M2-AMA), and not all AMA specificities are associated with PBC. The aim of the present study was to show the usefulness of the number and combination of subunits-specific AMA positive for the diagnosis of PBC. We detected AMA by indirect immunofluorescence (IIF-AMA) and M2-AMA by dot-blot. We studied the relationship of AMA with some clinical and laboratory variables in 307 patients (37% PBC) with positive dot-blot for M2-AMA. In PBC patients, we detected different E2 subunits of the 2-oxo acid dehydrogenase complexes antibodies (M2-AMA): 82.9% were specific for nPDC, 64.5% for PDC-E2, 44.4% for BCOADC-E2, and 9.6% for OGDC-E2. IIF and dot-blot tests achieved an Area Under the Receiver Operating Characteristic Curve (ROC AUC) of 0.674 (1:320 cut-off titer, Sensibility (Se) 64.7%, Specificity (Sp) 63.4%) and 0.663 (three specificities M2-AMA, Se 43%, Sp 81.2%), respectively. The detection of different E2 subunits of the 2-oxo acid dehydrogenase complexes antibodies (M2-AMA) by dot-blot showed different ROC AUC: anti-PDC-E2 showed an AUC of 0.610, a Se of 43.7%, and a Sp of 76.4%. Finally, the combined detection of nPDC/BCOADC-E2/PDC-E2 reached an AUC of 0.6095, a Se of 59.6%, and a Sp of 70.2%.The identification of two M2-AMA specificities through dot-blot increased PBC odds ratio (OR) by 2.05 (p:0.031), as compared to the identification of one specificity. Moreover, the identification of three and four specificities increased OR by 4.63 (p:0.000) and by 21.53 (p:0.006), respectively. nPDC/OGDC-E2/PDC-E2 and nPDC/OGDC-E2/BCOADC-E2/PDC-E2 combinations increased PBC OR by 10.04 (p:0.034), as compared to any other combination. 1:320 and 1:640 IIF-AMA increased PBC OR by 4.93 (p:0.009) and 7.67 (p:0.001), respectively, as compared to IIF-AMA titers equal to or less than 1:160. M2-AMA dot-blot was less sensitive but more specific than IIF-AMA, with similar predictive capacity for PBC. Increased numbers of M2-AMA specificities clearly increased the risk of PBC. Some combinations were strongly related to PBC (nPDC/BCOADC-E2/PDC-E2), but others were not (one single M2-AMA, and nPDC plus PDC-E2). M2-AMA dot-blot was less sensitive but more specific than IIF-AMA, with similar predictive capacity for PBC. Increased numbers of M2-AMA specificities clearly increased the risk of PBC, being some combinations, such as nPDC/BCOADC-E2/PDC-E2, more related to PBC than others. Finally, the determination of the number of M2-AMA specificities was more useful than the particular subunit target for PBC diagnosis. In conclusion, the study of the number of M2-AMA specificities by dot-blot should definitely be considered for PBC diagnosis.

A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA

In patients with primary biliary cholangitis (PBC), the efficacy of budesonide, a synthetic corticosteroid displaying high first-pass metabolism, is unresolved. In a placebo-controlled, double-blind trial, we evaluated the added-value of budesonide in those with PBC and ongoing risk of progressive disease despite ursodeoxycholic acid (UDCA) treatment. We evaluated 62 patients with PBC who had histologically confirmed hepatic inflammatory activity, according to the Ishak score, and an alkaline phosphatase (ALP) >1.5× upper limit of normal (ULN), after at least 6 months of UDCA therapy. Participants were randomly assigned 2:1 to receive budesonide (9 mg/day) or placebo once daily, for 36 months, with UDCA treatment (12-16 mg/kg body weight/day) maintained. Primary efficacy was defined as improvement of liver histology with respect to inflammation and no progression of fibrosis. Secondary outcomes included changes in biochemical markers of liver injury. Recruitment challenges resulted in a study that was underpowered for the primary efficacy analysis. Comparing patients with paired biopsies only (n= 43), the primary histologic endpoint was not met (p >0.05). The proportion of patients with ALP <1.67×ULN, a ≥15% decrease in ALP and normal bilirubin was higher in the budesonide group than in the placebo group at 12, 24, and 36 months (p <0.05, each). In contrast to placebo, budesonide reduced mean ALP and 35% of budesonide-treated patients achieved normalisation of ALP (placebo 9%; p= 0.023). Serious adverse events occurred in 10 patients receiving budesonide and 7 patients receiving placebo. Budesonide add-on therapy was not associated with improved liver histology in patients with PBC and insufficient response to UDCA; however, improvements in biochemical markers of disease activity were demonstrated in secondary analyses. Around one-third of patients with primary biliary cholangitis (PBC) needs additional medical therapy alongside ursodeoxycholic acid (UDCA) treatment. In this clinical trial, the addition of the corticosteroid budesonide did not improve liver histology; there were however relevant improvements in liver blood tests. CLINICALTRIALS. NCT00746486.

Change in risk of primary biliary cholangitis is associated with the evolution of coal mining

Change in risk of primary biliary cholangitis is associated with the evolution of coal mining

Association between Smoking and Risk of Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis.

Studies have suggested that smokers may have a higher risk of primary biliary cholangitis (PBC) although the results have been inconsistent. This systematic review and meta-analysis aim to better characterize the risk of PBC among smokers by identifying all relevant studies and summarizing their results together. A comprehensive literature review was conducted using Embase and Pubmed/MEDLINE databases from inception to September 2018 to identify all studies which compared the risk of PBC among current, ever and former smokers to non-smokers. Effect estimates from each study were extracted and combined together using the random-effect, generic inverse variance method of DerSimonian and Laird. Nine case-control studies with 21,577 participants met the eligibility criteria and were included in the meta-analysis. The risk of PBC among ever smokers was significantly higher than non-smokers with the pooled odds ratio (OR) of 1.31 (95% CI, 1.03-1.67; I 2 89%). Subgroup analysis found that the risk was higher in both former smokers (pooled OR 1.36; 95% CI, 1.01-1.84; I 2 75%) and current smokers (pooled OR 1.18; 95% CI, 0.94-1.50; I 2 79%), although the latter did not reach statistical significance. Immunomodulatory and cytotoxic effect of cigarettes were the possible mechanisms behind this increased risk. A significantly increased risk of PBC among individuals who ever smoked was observed in this study, adding to the already long list of harmful health consequences of smoking.

Mo1482 – Association Between Smoking and Risk of Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis

Mo1482 – Association Between Smoking and Risk of Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis

Primary biliary cholangitis in patients with systemic sclerosis: Unmasking the true face of Reynold's syndrome

Aim of the workHepatic involvement is uncommon in patients with SSc and often associated with primary biliary cholangitis (PBC) an association known as 'Reynold's syndrome'. Anti-mitochondrial antibody (AMA) and anti-centromere antibody (ACA) indicate increased PBC risk in SSc patients. This study aimed to evaluate the relationship between SSc and PBC, and also associated antibodies. Patients and methodsIn this study, 128 SSc patients with diffuse cutaneous (dcSSc n = 59) and limited cutaneous (lcSSc n = 69) subtypes were enrolled. PBC was diagnosed with any 2 of the following: cholestasis based on alkaline phosphatase elevation, presence of AMA and histologic evidence of destruction of interlobular bile ducts and nonsuppurative destructive cholangitis. ResultsThe mean age of the patients was 54.8 ± 13.2 years and disease duration 2.4 ± 1.4 years and they were 106 (82.8%) females and 22 males. ANA was positive in 80.4% of all patients, anti-Scl-70 in 36.7% and ACA in 37.5%. PBC was present in 8 patients (4 in each subtype). In patients with PBC, ACA was positive in 75% compared to 35% in those without (p = 0.03). The gamma-glutamyltransferase (GGT) and direct bilirubin were significantly higher in those with Reynolds syndrome (57.5 ± 26.9 U/L and 0.3 ± 0.1 mg/dl) compared to those without (19.7 ± 9.7 U/L and 0.19 ± 0.1 mg/dl; p < 0.001 and p = 0.02 respectively). A significant relation was found between AMA-M2 with AMA and ACA (p = 0.02). ConclusionAutoantibodies may provide information about organ involvement in SSc. AMA, AMA-M2, and ACA may predict hepatic disease in asymptomatic SSc patients with elevated GGT levels.

Coronary flow reserve in patients with primary biliary cholangitis

BackgroundIt is still not clear whether primary biliary cholangitis (PBC) is associated with abnormalities of the cardiovascular system. We aimed to assess the relationship between PBC and coronary flow reserve (CFR). MethodsOur inclusion criterion was a diagnosis of PBC with no clinical evidence of heart disease or metabolic syndrome. Coronary flow velocity in the left anterior descending coronary artery was measured using transthoracic Doppler echocardiography at rest (DFVr), and during adenosine infusion (DFVh). The corrected CFR (cCFR) was defined as the ratio of DFVh to DFVr corrected for cardiac workload (cDFVr). Microvascular resistance was also assessed in baseline (BMR) and hyperemic conditions (HMR). Results37 PBC patients and 37 sex- and age-matched controls were considered. The cCFR was significantly lower in PBC patients (2.8 ± 0.7 vs. 3.7 ± 0.7, p < 0.0001), and abnormal (≤2.5) in 13 (35%) of them, but in none of the controls (p < 0.0001). The cDFVr was higher in patients with abnormal cCFR (29.0 ± 6.0 vs. 20.4 ± 4.5 cm/sec, p < 0.0001). The CFR and cCFR did not correlate with any characteristics of PBC, comorbidities or Framingham risk scores. The BMR and HMR correlated with time since PBC diagnosis and duration of symptoms. ConclusionThe CFR is reduced in PBC, apparently due to mechanisms correlating with the time since diagnosis. In particular, the higher cDFVr with a lower basal resistance in patients with cCFR ≤ 2.5 suggests a compensatory mechanism against any cardiomyocyte bioenergetics impairment.

Association between STAT4 polymorphisms and risk of primary biliary cholangitis: a meta-analysis.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease. Several studies reported that SATA4 (signal transducer and activator of transcription 4) polymorphisms were significantly associated with PBC susceptibility. In order to derive a more comprehensive estimation of the association between STAT4 and PBC risk, this meta-analysis was conducted. Thirteen eligible studies from 8 articles with a total number of 11,310 cases and 27,844 controls were included in this meta-analysis. Pooled odds ratios (OR) and 95% confidence intervals (CI) were estimated with fixed effects model or random effects model. The results showed statistically significant association between polymorphisms of rs7574865, rs3024921, rs6752770, rs7601754 and rs10168266 in STAT4 and PBC risk under the allelic effect model (rs7574865, T vs. G, OR = 1.24, 95% CI 1.14-1.35; rs3024921, T vs. A, OR = 1.65, 95% CI 1.44-1.91; rs6752770, G vs. A, OR = 1.24, 95% CI 1.11-1.39; rs7601754, A vs. G, OR = 1.35, 95% CI 1.17-1.55; and rs10168266, T vs. C, OR = 1.31, 95% CI 1.22-1.41). Furthermore, the rs7574865 polymorphism was significantly associated with PBC risk under all genotype genetic models (dominant effect model: TT + TG vs. GG, OR = 1.43, 95% CI 1.19-1.71; recessive effect: TT vs. TG + GG, OR = 1.40, 95% CI 1.24-1.58; and co-dominant effect: TT vs. GG, OR = 1.67, 95% CI 1.37-2.02). The sensitivity analysis by omitting one study at a time showed that the results were stable. No publication bias was indicated from both Begg's test and Egger's weighted regression. This meta-analysis suggested that polymorphisms of rs7574865, rs3024921, rs6752770, rs7601754 and rs10168266 in STAT4 were significantly associated with the risk of PBC.

Genome-wide haplotype association analysis of primary biliary cholangitis risk in Japanese

Primary biliary cholangitis (PBC) susceptibility loci have largely been discovered through single SNP association testing. In this study, we report genic haplotype patterns associated with PBC risk genome-wide in two Japanese cohorts. Among the 74 genic PBC risk haplotype candidates we detected with a novel methodological approach in a discovery cohort of 1,937 Japanese, nearly two-thirds were replicated (49 haplotypes, Bonferroni-corrected P < 6.8 × 10−4) in an independent Japanese cohort (N = 949). Along with corroborating known PBC-associated loci (TNFSF15, HLA-DRA), risk haplotypes may potentially model cis-interactions that regulate gene expression. For example, one replicated haplotype association (9q32–9q33.1, OR = 1.7, P = 3.0 × 10−21) consists of intergenic SNPs outside of the human leukocyte antigen (HLA) region that overlap regulatory histone mark peaks in liver and blood cells, and are significantly associated with TNFSF8 expression in whole blood. We also replicated a novel haplotype association involving non-HLA SNPs mapped to UMAD1 (7p21.3; OR = 15.2, P = 3.9 × 10−9) that overlap enhancer peaks in liver and memory Th cells. Our analysis demonstrates the utility of haplotype association analyses in discovering and characterizing PBC susceptibility loci.

Using the Icelandic genealogical database to define the familial risk of primary biliary cholangitis.

Relatives of PBC patients had markedly higher risk for development of the disease compared with controls and importantly our data demonstrate that the risk was significantly increased even in second- and third-degree relatives. (Hepatology 2018;68:166-171).

A genome-wide association study identifies six novel risk loci for primary biliary cholangitis

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.

Genetic Polymorphisms of Cytotoxic T-Lymphocyte Antigen 4 in Primary Biliary Cholangitis: A Meta-Analysis.

Background and Aim The connection between gene polymorphisms of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and primary biliary cholangitis (PBC) is still vague and blurred. The purpose of this study is to precisely estimate the association of the polymorphisms of CTLA4 with the risk of PBC by using a meta-analysis. Methods PubMed and the Chinese National Knowledge Infrastructure (CNKI) database were used to search correlative literatures, and the documents which were about the relationships between the polymorphisms of CTLA4 (rs231775, rs231725, rs3087243, and rs5742909) and PBC were collected as of June 2016. The strength of correlation based on odds ratios (ORs) and its 95% confidence intervals (95%CIs) was computed by STATA. Results Generally, in rs231775, a significant risk was found in G allele, the value of OR was 1.32, and its 95%CI was 1.19 to 1.47. The same situation was found in A allele of rs231725, the value of OR was 1.33, and its 95%CI was 1.22 to 1.45. As genotypic level, different genotypic models were also found to have obvious relevance with PBC in rs231775 and rs231725. No obvious connections were found in other SNPs. Conclusion This study indicated that the polymorphisms of rs231775 and rs231725 would be the risk factors of PBC.

Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn's disease and leprosy.

Genetic polymorphism within the 9q32 locus is linked with increased risk of several diseases, including Crohn’s disease (CD), primary biliary cholangitis (PBC) and leprosy. The most likely disease-causing gene within 9q32 is TNFSF15, which encodes the pro-inflammatory cytokine TNF super-family member 15, but it was unknown whether these disparate diseases were associated with the same genetic variance in 9q32, and how variance within this locus might contribute to pathology. Using genetic data from published studies on CD, PBC and leprosy we revealed that bearing a T allele at rs6478108/rs6478109 (r2 = 1) or rs4979462 was significantly associated with increased risk of CD and decreased risk of leprosy, while the T allele at rs4979462 was associated with significantly increased risk of PBC. In vitro analyses showed that the rs6478109 genotype significantly affected TNFSF15 expression in cells from whole blood of controls, while functional annotation using publicly-available data revealed the broad cell type/tissue-specific regulatory potential of variance at rs6478109 or rs4979462. In summary, we provide evidence that variance within TNFSF15 has the potential to affect cytokine expression across a range of tissues and thereby contribute to protection from infectious diseases such as leprosy, while increasing the risk of immune-mediated diseases including CD and PBC.