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Background: Primary sclerosing cholangitis (PSC) is a rare, chronic cholestatic liver disease that often progresses to end-stage liver disease and/or the development of hepatobiliary neoplasia. Lack of prognostic tools and treatment options for PSC is driven in part by our poor understanding of its pathogenesis, which is thought to be complex, the interaction of genetic variants, environmental influences and biological response throughout the course of disease. The PSC Scientific Community Resource (PSC-SCR) seeks to overcome previous shortcomings by facilitating novel research in PSC with the ultimate goals of individualizing patient care and improving patient outcomes.Methods: PSC patients who receive their health care at Mayo Clinic or a collaborating site are identified by chart review and invited in person or by mail to participate. Non-Mayo patients are offered enrollment if they provide sufficient access to their medical records to evaluate inclusion/exclusion criteria. Controls without liver disease are identified with assistance of the Mayo Clinic Biobank. Participant consent is obtained at the beginning of the recruitment process by mail-in, electronic or face-to-face protocols. Clinical data is extracted from the medical record by qualified physicians and entered in a custom designed database. Participants fill out a custom-designed, comprehensive questionnaire, which collects scientifically relevant demographic and clinical information. Biospecimens are collected using mail-in kits thar are returned via overnight carrier service and processed by the biospecimen accessioning and processing facility at Mayo Clinic, which coordinates sample transfers and provides required sample preparation services. The resource is currently being utilized to perform omics-scale projects investigating the exposome, metabolome, methylome, immunome and microbiome in PSC. Datasets and residual biospecimens will be shared with researchers proposing scientifically sound PSC-focused research with approval of the appropriate review boards.Discussion: Patient-based studies leveraging the latest technologies for targeted and wide-scale interrogation of multiple omics layers offer promise to accelerate PSC research through discovery of unappreciated aspects of disease pathogenesis. However, the rarity of PSC severely limits such studies. Here we describe our effort to overcome this limitation, the PSC-SCR, a repository of patient biospecimens coupled with clinical and omics data for use by the broader PSC research community. [ABSTRACT FROM AUTHOR]

Background: Quantification of circulating organ-specific cell-free DNA (cfDNA) provides a sensitive measure of ongoing cell death that could benefit evaluation of the cholestatic liver diseases primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), which lack reliable non-invasive biomarkers. Our goal in this pilot study was to determine whether liver-specific cfDNA levels are increased in PBC and PSC patients relative to controls and in advanced versus early disease, to evaluate their potential as novel disease biomarkers.Methods: Peripheral blood derived bisulfite-treated DNA was PCR amplified from patients with PBC (n = 48), PSC (n = 48) and controls (n = 96) to evaluate methylation status at 16 CpG sites reported to be specifically unmethylated in liver tissue near the genes IGF2R, ITIH4 and VTN. Amplicons were used to prepare paired end libraries which were sequenced on a MiSeq sequencer. Trimmed reads were aligned and used to determine unmethylation ratios and to calculate concentration of liver-specific cfDNA. Comparisons between groups were performed using the two-tailed Mann-Whitney Test and relationships between variables were evaluated using Pearson's Correlation.Results: Levels of liver-specific cfDNA, as measured at the 3 genetic loci, were increased in PBC and PSC patients relative to controls and in late-stage relative to early-stage patients. As well, cfDNA levels were correlated with levels of alkaline phosphatase, a commonly used biochemical test to evaluate disease severity in liver disease, in patients, but not in controls.Conclusions: cfDNA offers promise as a non-invasive liquid-biopsy to evaluate liver-specific cell-death in patients with cholestatic liver diseases. [ABSTRACT FROM AUTHOR]

The relationship between primary biliary cholangitis (PBC), a chronic cholestatic autoimmune liver disease, and the peripheral immune system remains to be fully understood. Herein, we performed the first mass cytometry (CyTOF)-based, immunophenotyping analysis of the peripheral immune system in PBC at single-cell resolution. CyTOF was performed on peripheral blood mononuclear cells (PBMCs) from PBC patients (n = 33) and age-/sex-matched healthy controls (n = 33) to obtain immune cell abundance and marker expression profiles. Hierarchical clustering methods were applied to identify immune cell types and subsets significantly associated with PBC. Subsets of gamma-delta T cells (CD3+TCRgd+), CD8+ T cells (CD3+CD8+CD161+PD1+), and memory B cells (CD3−CD19+CD20+CD24+CD27+) were found to have lower abundance in PBC than in control. In contrast, higher abundance of subsets of monocytes and naïve B cells were observed in PBC compared to control. Furthermore, several naïve B cell (CD3−CD19+CD20+CD24−CD27−) subsets were significantly higher in PBC patients with cirrhosis (indicative of late-stage disease) than in those without cirrhosis. Alternatively, subsets of memory B cells were lower in abundance in cirrhotic relative to non-cirrhotic PBC patients. Future immunophenotyping investigations could lead to better understanding of PBC pathogenesis and progression, and also to the discovery of novel biomarkers and treatment strategies. [ABSTRACT FROM AUTHOR]

Background & Aims Primary biliary cirrhosis ( PBC) is characterized by chronic cholestasis and disease-specific antimitochondrial antibodies ( AMA). A high prevalence of AMAs in first-degree relatives ( FDRs) of PBC probands has been reported, although the natural history of such patients has not been described. We aimed to assess the risk of developing PBC in AMA+ FDRs of patients with PBC. Methods First-degree relatives recruited to the Mayo Clinic PBC Genetic Epidemiology Registry and Biorepository were followed for disease onset after recruitment. Development of PBC was ascertained via self-report during a telephone interview and/or via proband report on a questionnaire. Chi-squared test and t-test were used to assess the differences between categorical and continuous variables respectively. A mixed-effects model was used to assess the change in biochemical profiles over time. Results Forty AMA+ and 423 AMA− subjects were included and followed for a median of 8.9 and 8.4 years respectively. Overall, 3% ( n = 15) of FDRs were diagnosed with PBC, and AMA+ FDRs had a higher risk than AMA− FDRs (24% vs. 0.7%, P < 0.01). However, among undiagnosed FDRs, only 4% of AMA+ ( n = 1) and 0.4% of AMA− ( n = 1) FDRs were diagnosed with PBC ( P = 0.17) during the follow-up period. None of the AMA+ FDRs with normal alkaline phosphatase at baseline developed PBC in follow-up. Conclusions Our results suggest a low risk of developing PBC over time in FDRs of patients with PBC, particularly those without biochemical evidence of cholestasis at baseline. These data are useful in counselling and reassuring relatives of their overall favourable prognosis. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWASs) have been a significant technological advance in our ability to evaluate the genetic architecture of complex diseases such as primary biliary cirrhosis (PBC). To date, six large-scale studies have been performed that have identified 27 risk loci in addition to human leukocyte antigen (HLA) associated with PBC. The identified risk variants emphasize important disease concepts; namely, that disturbances in immunoregulatory pathways are important in the pathogenesis of PBC and that such perturbations are shared among a diverse number of autoimmune diseases--suggesting the risk architecture may confer a generalized propensity to autoimmunity not necessarily specific to PBC. Furthermore, the impact of non-HLA risk variants, particularly in genes involved with interleukin-12 signaling, and ethnic variation in conferring susceptibility to PBC have been highlighted. Although GWASs have been a critical stepping stone in understanding common genetic variation contributing to PBC, limitations pertaining to power, sample availability, and strong linkage disequilibrium across genes have left us with an incomplete understanding of the genetic underpinnings of disease pathogenesis. Future efforts to gain insight into this missing heritability, the genetic variation that contributes to important disease outcomes, and the functional consequences of associated variants will be critical if practical clinical translation is to be realized. [ABSTRACT FROM AUTHOR]

Genetic risk factors for cholangiocarcinoma ( CCA) remain poorly understood. We assessed the effect of single-nucleotide polymorphisms ( SNPs) of genes modulating inflammation or carcinogenesis on CCA risk and survival. We conducted a case-control, candidate gene association study of 370 CCA patients and 740 age-, sex-, and residential area-matched healthy controls. Eighteen functional or putatively functional SNPs in nine genes were genotyped. The log-additive genotype effects of SNPs on CCA risk and survival were determined using logistic regression and the log-rank test, respectively. Initial analysis identified significant associations between SNP rs2143417 and rs689466 in cyclooxygenase 2 ( COX-2) and CCA risk, after adjusting for multiple comparisons (cutoff of P = 0.0028). However, these findings were not replicated in another independent cohort of 212 CCA cases and 424 matched controls. No significant association was found between any SNP and survival of CCA patients. Although COX-2 has been shown to contribute to cholangiocarcinogenesis, the COX-2 SNPs tested were not associated with risk of CCA. This study shows a lack of association between variants of genes related to inflammation and carcinogenesis and CCA risk and survival. Other factors than these genetic variants may play more important roles in CCA risk and survival. [ABSTRACT FROM AUTHOR]

The etiology of the autoimmune liver disease primary biliary cirrhosis (PBC) remains largely unresolved, owing in large part to the complexity of interaction between environmental and genetic contributors underlying disease development. Observations of disease clustering, differences in geographical prevalence, and seasonality of diagnosis rates suggest the environmental component to PBC is strong, and epidemiological studies have consistently found cigarette smoking and history of urinary tract infection to be associated with PBC. Current evidence implicates molecular mimicry as a primary mechanism driving loss of tolerance and subsequent autoimmunity in PBC, yet other environmentally influenced disease processes are likely to be involved in pathogenesis. In this review, the authors provide an overview of current findings and touch on potential mechanisms behind the environmental component of PBC. [ABSTRACT FROM AUTHOR]

Background : Primary sclerosing cholangitis (PSC) patients have a risk of developing cholangiocarcinoma (CCA). Establishing predictive models for CCA in PSC is important. Methods: In a large cohort of 1,459 PSC patients seen at Mayo Clinic (1993–2020), we quantified the impact of clinical/laboratory variables on CCA development using univariate and multivariate Cox models and predicted CCA using statistical and artificial intelligence (AI) approaches. We explored plasma bile acid (BA) levels' predictive power of CCA (subset of 300 patients, BA cohort). Results: Eight significant risk factors (false discovery rate: 20%) were identified with univariate analysis; prolonged inflammatory bowel disease (IBD) was the most important one. IBD duration, PSC duration, and total bilirubin remained significant (p < 0.05) with multivariate analysis. Clinical/laboratory variables predicted CCA with cross-validated C-indexes of 0.68–0.71 at different time points of disease, significantly better compared to commonly used PSC risk scores. Lower chenodeoxycholic acid, higher conjugated fraction of lithocholic acid and hyodeoxycholic acid, and higher ratio of cholic acid to chenodeoxycholic acid were predictive of CCA. BAs predicted CCA with a cross-validated C-index of 0.66 (std: 0.11, BA cohort), similar to clinical/laboratory variables (C-index = 0.64, std: 0.11, BA cohort). Combining BAs with clinical/laboratory variables leads to the best average C-index of 0.67 (std: 0.13, BA cohort). Conclusions: In a large PSC cohort, we identified clinical and laboratory risk factors for CCA development and demonstrated the first AI based predictive models that performed significantly better than commonly used PSC risk scores. More predictive data modalities are needed for clinical adoption of these models. [ABSTRACT FROM AUTHOR]

The damaging cholestasis inherent to primary sclerosing cholangitis (PSC) results from bile duct stricturing because of progressive fibrosis. The matrix metalloproteinase 3 (MMP3) degrades a wide range of matrix components and is expressed by activated liver stellate cells, and so is a candidate for involvement with the fibrotic processes underlying PSC. Moreover, the MMP3 gene harbours polymorphisms associated with variation in its activity directly impacting clinical phenotypes. We aimed to examine the influence of MMP3 polymorphisms on PSC risk and progression. Nine single nucleotide polymorphisms (SNPs) tagging the common genetic variation of MMP3 were genotyped in 266 PSC patients and 407 controls. SNPs and inferred haplotypes were assessed for PSC association by logistic regression and score tests. The effect of SNPs on survival to liver transplant or death was analysed using Cox regression, and Kaplan-Meier curves were constructed. No association of PSC with individual SNPs or haplotypes of MMP3 was detected. However, progression to death or liver transplant was significantly associated with homozygosity for minor alleles of rs522616, rs650108 and rs683878, particularly among PSC patients with concurrent ulcerative colitis (UC) (strongest in redundant SNPs rs650108/rs683878, hazard ratio=3.23, 95% confidence interval 1.45-7.25, P=0.004). Genetic variation in MMP3 influences PSC progression, possibly in the context of coexisting UC. While the functional variants and specific mechanisms remain unknown, this finding implicates the turnover of the extracellular matrix as an important and variable component of PSC pathogenesis. Efforts to understand this process could form the basis for developing effective treatments, which are currently lacking for PSC. [ABSTRACT FROM AUTHOR]

Abstract: Despite recent progress, the pathogenic mechanisms governing PBC development, treatment response and outcome remain unknown. This deficiency is in large part due to the complex nature of PBC, wherein various environmental factors may be capable of prompting disease, but only in the context of underlying genetic susceptibility. Identification of genomic loci containing these heritable risk factors has been slowed by the rarity and late onset of PBC, which has made difficult the collection of sufficient numbers of patients and family members for meaningful genetic analyses. Advancements in our ability to catalog the genetic variation in large numbers of individuals at a genome-wide scale, coupled with unprecedented efforts to recruit PBC patients for genetic study, positions us to generate data that could fundamentally change our understanding of PBC and lead to clinical innovation. Indeed, the first genome-wide association study for PBC has been published, in which multiple genes involved with IL12 signaling, a pathway that is being targeted in treatment of other inflammatory conditions, were implicated in disease. However, this study was relatively small in the genome-wide milieu and a significantly expanded effort will be necessary to truly elucidate the genetic architecture of PBC. Moving ahead, cooperation between the groups collecting biospecimens and generating genome-wide data from large numbers of patients with PBC will be essential, not only to increase power for fine mapping and future studies of rare variants and epistasis; but to streamline efforts to perform functional validation of novel discoveries. Here we provide a brief update of the current state of genetics in PBC to form a basis for understanding the considerable progress that is likely to be made in the coming years. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Deficiencies of the anion exchanger SLC4A2 are thought to play a pathogenic role in primary biliary cirrhosis (PBC), as the evidenced by decreased expression and activity in PBC patients and development of disease features in SLC4A2 knockout mice. We hypothesized that genetic variation in SLC4A2 might influence this pathogenic contribution. Thus, we aimed to perform a comprehensive assessment of SLC4A2 genetic variation in PBC using a linkage disequilibrium (LD)-based haplotype-tagging approach.METHODS:Twelve single nucleotide polymorphisms (SNPs) across SLC4A2 were genotyped in 409 PBC patients and 300 controls and evaluated for association with disease, as well as with prior orthotopic liver transplant and antimitochondrial antibody (AMA) status among the PBC patients, both individually and as inferred haplotypes, using logistic regression.RESULTS:All SNPs were in Hardy–Weinberg equilibrium. No associations with disease or liver transplantation were detected, but two variants, rs2303929 and rs3793336, were associated with negativity for antimitochondrial antibodies among the PBC patients.CONCLUSIONS:The common genetic variation of SLC4A2 does not directly affect the risk of PBC or its clinical outcome. Whether the deficiency of SLC4A2 expression and activity observed earlier in PBC patients is an acquired epiphenomenon of underlying disease or is because of heritable factors in unappreciated regulatory regions remains uncertain. Of note, two SLC4A2 variants appear to influence AMA status among PBC patients. The mechanisms behind this finding are unclear.Am J Gastroenterol 2009; 104:1406–1411; doi:10.1038/ajg.2009.103; published online 21 April 2009 [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3 , INAVA , PRDM1 , IRF7 , CCR6 , CD226 , and IL12RB1 , which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (T H)1 and T H 17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these 'candidate genes' to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC. [Display omitted] • Trans-ethnic genome-wide meta-analysis (GWMA) of susceptibility to primary biliary cholangitis (PBC). • Five cohorts of European ancestry and two East Asian cohorts (n = 10,516 cases and 20,772 controls). • Identification of 21 additional risk loci for PBC. • Preliminary evidence that the genetic architecture of PBC is broadly shared across European and East Asian populations. • Identification (using in silico drug efficacy screening) of medications potentially suitable for re-purposing to PBC. [ABSTRACT FROM AUTHOR]

Background and Aim Primary sclerosing cholangitis (PSC) typically develops in middle-age adults. Little is known about phenotypic differences when PSC is diagnosed at various ages. Therefore, we sought to compare the clinical characteristics of a large PSC cohort based on the age when PSC was diagnosed. Methods We performed a multicenter retrospective review to compare the features of PSC among those diagnosed between 1-19 ( n = 95), 20-59 ( n = 662), and 60-79 years ( n = 102). Results Those with an early diagnosis (ED) of PSC were more likely to have small-duct PSC (13%) than those with a middle-age diagnosis (MD) (5%) and late diagnosis (LD) groups (2%), P < 0.01, and appeared to have a decrease risk of hepatobiliary malignancies: ED versus MD: hazard ratio (HR), 0.25; 95% confidence interval (CI) 0.06-1.03, and ED versus LD: HR, 0.07; 95% CI 0.01-0.62. Cholangiocarcinoma was diagnosed in 78 subjects (ED n = 0, MD n = 66, and LD n = 12) and was more likely to be diagnosed within a year after the PSC diagnosis among those found to have PSC late in life: ED 0% (0/95), MD 2% (14/662), and LD 6% (6/102), P = 0.02. Similarly, hepatic decompensation was more common among those with LD-PSC versus younger individuals: LD versus MD: HR, 1.64; 95% CI 0.98-2.70, and LD versus ED: HR, 2.26; 95% CI 1.02-5.05. Conclusions Those diagnosed with PSC early in life are more likely to have small-duct PSC and less likely to have disease-related complications. Clinicians should be vigilant for underlying cholangiocarcinoma among those with PSC diagnosed late in life. [ABSTRACT FROM AUTHOR]

Background & Aims: Small duct primary sclerosing cholangitis (PSC) is phenotypically a mild version of large duct PSC, but it is unknown whether these phenotypes share aetiology. We aimed to characterize their relationship by investigating genetic associations in the human leucocyte antigen (HLA) complex, which represent the strongest genetic risk factors in large duct PSC. Methods: Four classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped in 87 small duct PSC patients, 485 large duct PSC patients and 1117 controls across three geographical regions. Results: HLA-DRB1*13:01 (OR = 2.0, 95% CI 1.2–3.4, P = 0.01) and HLA-B*08 (OR = 1.6, 95% CI 1.1–2.4, P = 0.02) were significantly associated with small duct PSC compared with healthy controls. Based on the observed frequency of HLA-B*08 in small duct PSC, the strongest risk factor in large duct PSC, an estimated 32% (95% CI 4–65%) of this population can be hypothesized to represent early stages or mild variants of large duct PSC. This subgroup may be constituted by small duct PSC patients with inflammatory bowel disease (IBD), which greatly resembled large duct PSC in its HLA association. In contrast, small duct PSC without IBD was only associated with HLA-DRB1*13:01(P = 0.03) and was otherwise distinctly dissimilar from large duct PSC. Conclusions: Small duct PSC with IBD resembles large duct PSC in its HLA association and may represent early stages or mild variants of large duct disease. Different HLA associations in small duct PSC without IBD could indicate that this subgroup is a different entity. HLA-DRB1*13:01 may represent a specific risk factor for inflammatory bile duct disease. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Background & Aims: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). Methods: We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Results: Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p replication <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p combined =2.1×10−8) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p repl <0.05). FUT2 at chromosome 19q13 (rs602662; p comb =1.9×10−6, rs281377; p comb =2.1×10−6 and rs601338; p comb =2.7× 10−6) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients. Conclusions: We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC. [Copyright &y& Elsevier]

Background: Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown. Methods: To identify genetic loci conferring a risk for primary biliary cirrhosis, we carried out a genomewide association analysis in which DNA samples from 2072 Canadian and U.S. subjects (536 patients with primary biliary cirrhosis and 1536 controls) were genotyped for more than 300,000 single-nucleotide polymorphisms (SNPs). Sixteen of the SNPs most strongly associated with primary biliary cirrhosis were genotyped in two independent replication sets. We carried out fine-mapping studies across three loci associated with primary biliary cirrhosis. Results: We found significant associations between primary biliary cirrhosis and 13 loci across the HLA class II region; the HLA-DQB1 locus (encoding the major histocompatibility complex class II, DQ β chain 1) had the strongest association (P=1.78×10−19; odds ratio for patients vs. controls, 1.75). Primary biliary cirrhosis was also significantly and reproducibly associated with two SNPs at the IL12A locus (encoding interleukin-12α), rs6441286 (P=2.42×10−14; odds ratio, 1.54) and rs574808 (P=1.88×10−13; odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor β2), rs3790567 (P=2.76×10−11; odds ratio, 1.51). Fine-mapping analysis showed that a five-allele haplotype in the 3′ flank of IL12A was significantly associated with primary biliary cirrhosis (P=1.15×10−34). We found a modest genomewide association (P<5.0×10−5) with the risk of disease for SNPs at the STAT4 locus (encoding signal transducer and activator of transcription 4) and the CTLA4 locus (encoding cytotoxic T-lymphocyte–associated protein 4) and 10 other loci. Conclusions: Our data show significant associations between primary biliary cirrhosis and common genetic variants at the HLA class II, IL12A, and IL12RB2 loci and suggest that the interleukin-12 immunoregulatory signaling axis is relevant to the pathophysiology of primary biliary cirrhosis. (ClinicalTrials.gov number, NCT00242125.) N Engl J Med 2009;360:2544-55. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively). [ABSTRACT FROM AUTHOR]

We genotyped individuals with primary biliary cirrhosis and unaffected controls for suggestive risk loci (genome-wide association P < 1 × 10−4) identified in a previous genome-wide association study. Combined analysis of the genome-wide association and replication datasets identified IRF5-TNPO3 (combined P = 8.66 × 10−13), 17q12-21 (combined P = 3.50 × 10−13) and MMEL1 (combined P = 3.15 × 10−8) as new primary biliary cirrhosis susceptibility loci. Fine-mapping studies showed that a single variant accounts for the IRF5-TNPO3 association. As these loci are implicated in other autoimmune conditions, these findings confirm genetic overlap among such diseases. [ABSTRACT FROM AUTHOR]