Original Article
Primary Biliary Cirrhosis Associated with HLA, IL12A, and IL12RB2 Variants
N Engl J Med 2009; 360:2544-2555June 11, 2009
- Abstract
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.)
Media in This Article
Figure 1
Quality Control and Study Design.Figure 2
Results of the Genomewide Association Analysis.Article Activity
- Article
Primary biliary cirrhosis is the most common autoimmune liver disease, affecting up to 1 in 1000 women over 40 years of age.1 Treatment for this chronic cholestatic condition remains empirical.2 The granulomatous destruction of interlobular bile ducts that characterizes primary biliary cirrhosis is almost always associated with antimitochondrial antibodies specific for the E2 subunit of the pyruvate dehydrogenase complex.3 The hepatic accumulation of autoreactive T lymphocytes in patients with primary biliary cirrhosis, as well as data from animal models of autoimmune cholangitis, implicate T lymphocytes — CD4+ T helper lymphocytes in particular — in the pathogenesis of primary biliary cirrhosis.4-6
A genetic predisposition for primary biliary cirrhosis has been revealed by analysis of both aggregation data from families and concordance data from twins. The rate of concordance among monozygotic twins is 60%,7 with the sibling relative risk estimated as 10.5.8 The coexistence of other autoimmune diseases in patients and the increased prevalence of such diseases in their families is also consistent with a genetic influence.9,10 Among the genes studied as susceptibility candidates, only HLA has consistently been associated with primary biliary cirrhosis. HLA-DRB1*0801 confers an increased risk of primary biliary cirrhosis in whites, with an odds ratio of 2.4 to 3.3. In addition, the derived population attributable fraction for HLA-DRB1*08 ranges from 2.8 to 8.8%11,12 (for the derivation, see the Supplementary Appendix, available with the full text of this article at NEJM.org). Primary biliary cirrhosis has also been associated — in some, but not all, studies — with variants in CTLA4 (the gene encoding cytotoxic T-lymphocyte–associated protein 4).13-15 To explore the genetic basis of primary biliary cirrhosis, we conducted genomewide association screening of subjects from North America.
Methods
Patients and Controls
We used a two-stage design to analyze data from 2072 white subjects (536 patients and 1536 controls) from North America (Figure 1Figure 1
Quality Control and Study Design.). Stage 1 consisted of a genomewide association survey of patients with primary biliary cirrhosis and controls from Canada, with additional historical controls from the United States. We carried out replication analyses (stage 2) involving patients and controls from the United States (stage 2a) and additional patients and controls from Canada (stage 2b), as well as fine-mapping studies of all Canadian subjects from the genomewide association screening (stage 1) and replication analysis (stage 2b). We obtained written informed consent from all subjects, and the study was approved by a local institutional ethics committee at each center.All patients fulfilled the criteria of the American Association for the Study of Liver Diseases for primary biliary cirrhosis,16 and all patients and controls were whites of European origin (as determined by self-report and, for patients included in stage 1, confirmed by genotyping; see the Supplementary Appendix). Data from a total of 536 patients with primary biliary cirrhosis and 1536 healthy controls (399 healthy volunteers in Toronto who had no history of autoimmune disease, and an additional 1137 historical controls from an M.D. Anderson lung cancer study17) were included in the stage 1 genomewide association analysis. The stage 2a replication analysis included data from 410 patients with primary biliary cirrhosis and 310 controls from the Mayo Clinic Primary Biliary Cirrhosis Registry,14 and stage 2b included data from additional subjects in Canada (116 patients and 896 controls). The genomic data from the Canadian patients and controls in stage 1, which were subject to quality-control standards, and stage 2b (the additional 116 patients and 896 controls in Canada) were included in the fine-mapping analyses. Data from all patients and controls (in stages 1, 2a, and 2b) were included in the combined analysis.
Genotyping and Quality Control
DNA purification and genotyping methods are described in the Supplementary Appendix. In stage 1, samples from the patients and the Canadian controls were genotyped for 373,400 single-nucleotide polymorphisms (SNPs) with the use of the Illumina HumanHap370 BeadChip. Samples from the M.D. Anderson historical controls were genotyped on the Illumina HumanHap300 BeadChip. Genotyping data were subjected to quality control before the data analysis (see the Supplementary Appendix). Genotypes were called if they exceeded minimum quality-control standards. Individual samples with genotype call rates of less than 95% and SNPs with call rates of less than 95%, minor-allele frequencies of less than 1%, or deviation from the Hardy–Weinberg equilibrium at P<0.0001 were removed. Replication and fine-mapping were performed with the use of the Sequenom MassArray iPLEX genotyping platform.
Statistical Analysis
For the genomewide association analysis, pairwise identity-by-state analysis was performed with PLINK software (version 1.05)18 (http://pngu.mgh.harvard.edu/purcell/plink/) to identify subjects with excess identity-by-descent sharing (PI_HAT >0.25), a measure of the degree of genetic relationship between subjects. One subject from each of the 15 pairs exceeding this threshold was removed from the association analysis; the subject in each pair with the higher average SNP call rate was retained. Hierarchical cluster analysis was performed with the use of PLINK to identify subjects with similar genotypes over the entire genome; the 39 samples that were more than 4 SD from a nearest neighbor were removed from the analysis. Subsequent association analyses were conducted with the use of a conditional analysis adjusting for stratifications among groups of subjects identified by hierarchical clustering. To control alternatively for the potential confounding influences of population stratification, association analysis was also performed on the basis of a principal-components analysis implemented in the EIGENSTRAT method19 with default parameters, in which we adjusted for the 10 eigenvectors having the highest eigenvalues. The lambda values showed minimal inflation (1.085 before and 1.056 after adjustment for eigenvectors); with the use of PLINK, the lambda values were 1.14 without adjustment for clusters and 1.09 with adjustment for clusters.
Allele and genotype associations were assessed by means of PLINK software, and linkage disequilibrium between pairs of SNPs and haplotypes was determined with the use of Haploview software, version 4.1 (www.broad.mit.edu/mpg/haploview). Haplotype block structure was defined according to the criteria established by Gabriel et al.20 and the pairwise estimates of standardized Lewontin's disequilibrium coefficient (D′), whereas the linkage disequilibrium among pairs of SNPs was characterized according to the square of the correlation coefficient (r2).
Combined analyses were carried out with Cochran–Mantel–Haenszel tests and SAS software, with adjustment for potential confounding of the case or control frequency with genotype frequency among groups of subjects according to the stage of analysis or center. Supplementary analyses are described in the Supplementary Appendix.
Results
Genomewide Association Analysis (Stage 1)
The most significant results of the stage 1 genomewide association survey are shown in Table 1Table 1
Results of Genomewide Association (Stage 1) and Replication (Stage 2) Analyses. and Figure 2Figure 2Results of the Genomewide Association Analysis. and Figure 3Figure 3
Results of Association Analyses and Linkage-Disequilibrium Blocks for the IL12A and IL12RB2 Loci.. (The full set is available from the database of Genotypes and Phenotypes [dbGaP]; www.ncbi.nlm.nih.gov/sites/entrez?db=gap, accession number phs000183.v1.p1). The stage 1 results are based on the analysis of the 305,724 SNPs that passed quality-control standards and the 505 patients with primary biliary cirrhosis and 1507 controls who were retained after the pairwise identity-by-state analysis and correction for population stratification.Thirteen SNPs across the HLA region on chromosome 6p21.3 and three SNPs from two distinct non-HLA regions at the IL12A locus, which encodes interleukin-12α (3q25.33–q26), and the IL12RB2 locus, which encodes interleukin-12 receptor β2 (1p31.2), met a significance threshold for genomewide association of P<5.0×10−7 (calculated with the EIGENSTRAT method). The most significantly associated markers according to the EIGENSTRAT method — rs2856683, rs9275312, rs9275390, and rs7775228 — map to the region between the HLA-DQB1 gene, which encodes major histocompatibility complex (MHC) class II, DQ β chain 1, and the HLA-DQA2 gene, which encodes MHC class II, DQ α chain 2. The P values from the PLINK analysis for these associations were between 1.70×10−10 and 8.58×10−17, with odds ratios for patients as compared with controls that ranged from 1.81 to 2.01. Highly significant association signals (according to the PLINK analysis) were also shown for nine other SNPs mapping in or near genes within the HLA region: C6orf10, which encodes chromosome 6 open reading frame 10 (P=5.62×10−10); HLA-DPB1, which encodes MHC class II, DP β chain 1 (P=8.28×10−9); BTNL2, which encodes butyrophilin-like 2 (P=1.27×10−9); and HLA-DRA, which encodes MHC class II, DR α chain (P=6.83×10−7). The C6orf10 locus had the strongest association with the risk of primary biliary cirrhosis (odds ratio, 3.24). Haplotype analysis, however, revealed that 4 of the 13 SNPs (rs2395148, rs3135363, rs2856683, and rs9357152 [in the C6orf10, BTNL2, HLA-DQB1 and HLA-DQB1 genes, respectively]) accounted for all of the HLA-associated risk for primary biliary cirrhosis (Table 1 in the Supplementary Appendix). Similar levels of association were found in a separate analysis of the genomewide data from Canadian controls only (Table 2 in the Supplementary Appendix).
Among the non-HLA loci, the strongest signals of association with primary biliary cirrhosis were found for two SNPs in the IL12A locus, rs6441286 (P=3.25×10−8; odds ratio for patients vs. controls, 1.51) and rs574808 (P=5.34×10−7; odds ratio, 1.47), and one SNP in the IL12RB2 locus, rs3790567 (P=8.60×10−8; odds ratio, 1.54). A significant association with disease was also seen with a second IL12RB2-region SNP, rs3790565 (P=1.41×10−6).
Twelve other non-HLA loci with association signals at significance levels of P<5.0×10−5 were identified. These included STAT4, which encodes signal transducer and activator of transcription 4 (rs16833239, P=2.60×10−5), a locus associated with risks of several other autoimmune diseases and a downstream biologic mediator of interleukin-12 signaling22; CTLA4 (rs6748358, P=1.41×10−5), a locus previously associated with a risk of primary biliary cirrhosis14,15; and the IRF5–TNPO3 locus (encoding interferon regulatory factor 5 and transportin 3, respectively) (rs10488631) (P=2.14×10−5), which is associated with risk for systemic lupus erythematosus23 and inflammatory bowel disease.24 These 12 loci were more modestly associated with primary biliary cirrhosis than were the IL12A and IL12RB2 loci, but the associations with the disease risk were similar, with odds ratios for patients as compared with controls ranging from 1.38 to 2.13.
Independent Replication (Stage 2) and Combined Analysis
We tested for an association between disease and 16 of the most strongly associated SNPs from the stage 1 analysis, using two independently collected sets of case–control samples from subjects in the United States (stage 2a analysis) and Canada (stage 2b analysis). We found replication of the association (P<0.05 from the PLINK analysis in each replication cohort and P<0.05 with the Bonferroni correction in the joint replication analysis of both cohorts) with the rs2856683, rs2395148, and rs9277535 SNPs at three distinct sites within the HLA region as well as the rs6441286–rs574808 and rs3790567 SNPs at the IL12A and IL12RB2 loci, respectively.
A combined analysis of the genomewide association and replication data sets (from stages 1 and 2) also provided strong evidence (by means of a Cochran–Mantel–Haenszel test) of an association between primary biliary cirrhosis and the loci HLA-DQB1 (P=1.78×10−19; odds ratio for patients vs. controls, 1.75), C6orf10 (P=3.62×10−14; odds ratio, 2.87), HLA-DPB1 (P=3.92×10−11; odds ratio, 1.50), BTNL2 (P=1.11×10−9; odds ratio, 1.42), IL12A (P=2.42×10−14; odds ratio, 1.54), and IL12RB2 (P=2.76×10−11; odds ratio, 1.51). We found no significant effect of antimitochondrial-antibody status on these associations (Table 3 in the Supplementary Appendix). In addition, we found an increasing risk in association with increasing numbers of copies of risk alleles for the IL12A and IL12RB2 loci (Tables 4 and 5 in the Supplementary Appendix).
Fine-Mapping and Haplotype Analyses
To refine and further validate the two major non-HLA loci associated with primary biliary cirrhosis (IL12A and IL12RB2), we genotyped tag SNPs across these loci in samples from all Canadian patients and controls (Table 2Table 2
Results of Fine-Mapping and Haplotype Analyses for the IL12A and IL12RB2 Loci., and Table 6 in the Supplementary Appendix). To fine-map the IL12A locus, we genotyped 25 SNPs spanning 80 kb and encompassing the IL12A gene and the regions upstream (5′ end, 38 kb) and downstream (3′ end, 32 kb). We observed significant associations for multiple SNPs, with the strongest signal generated by rs4679868, downstream of IL12A (P=1.58×10−9; odds ratio for patients vs. controls, 1.55). This variant was not genotyped in stage 1. Through haplotype analyses (Table 7 in the Supplementary Appendix), we identified a five-allele haplotype, downstream of IL12A, comprising the rs4679867, rs4679868, rs6441286, rs574808, and rs589545 SNPs (TAGTG), as a major risk haplotype for primary biliary cirrhosis (P=4.82×10−29). A combined analysis of the Canadian and U.S. samples revealed the presence of this haplotype in 49.1% of all patients (vs. 32.0% of controls) and confirmed the significant association with disease (P=1.15×10−34; odds ratio, 2.01).To fine-map the IL12RB2 locus, we genotyped 39 tag SNPs spanning 176.1 kb across the region encompassing IL23R (the gene encoding the interleukin-23 receptor) and IL12RB2. Included in these tag SNPs were IL23R variants previously shown to be associated with Crohn's disease and psoriasis.25,26 SNPs in the intronic regions and regions downstream of IL12RB2 showed the strongest associations with primary biliary cirrhosis; rs6679356 showed the most significant association (P=7.02×10−8). Moreover, we observed a significant association between primary biliary cirrhosis and a three-SNP haplotype (GTC) downstream of IL12RB2 (present in 35.6% of patients and 25.3% of controls; P=3.07×10−11; odds ratio for patients vs. controls, 1.53) (Table 8 in the Supplementary Appendix). No significant associations were seen with IL23R SNPs.
Although the association between primary biliary cirrhosis and the rs16833239 SNP in STAT4 was not replicated, in the combined analysis the association was significant (P=4.67×10−5; odds ratio for patients vs. controls, 1.65), a finding that may be particularly relevant to the associations with markers implicating IL12A and IL12RB2. We therefore carried out additional genotyping of SNPs across the 94.6-kb STAT4 locus, finding modest associations between disease and several intronic SNPs. A SNP in intron 3, rs3024921, showed a significant association (P=5.76×10−8) in the combined data set (Tables 6 and 9 in the Supplementary Appendix).
Finally, we performed stepwise selection and conditional analysis of the SNPs from the fine-mapping analysis across the IL12A, IL12RB2, and STAT4 loci (Table 10 in the Supplementary Appendix). For each region, we found that multiple alleles underlie the observed associations.
Discussion
We have identified the HLA, IL12A, and IL12RB2 loci as susceptibility loci for primary biliary cirrhosis. Our study provides compelling evidence that all three loci are involved in primary biliary cirrhosis: the successful replication in independent cohorts of the most strongly associated SNP at each of these loci, the high significance levels in the combined analysis, and the identification (through ancillary genotyping) of several other SNPs across the IL12A and IL12RB2 loci that are associated with primary biliary cirrhosis.
Associations between primary biliary cirrhosis and MHC class II alleles have been reported12 but have been only inconsistently replicated in other studies. Our data provide conclusive evidence that this region is involved in primary biliary cirrhosis, with associations shown between disease and variants in the four HLA class II genes (DQB1, DPB1, DRB1, and DRA) and the C6orf10 and BTNL2 genes also at this locus. Among these genes, DQB1, DPB1, and DRB1 have previously been implicated in primary biliary cirrhosis,27 and the association of a BTNL2 truncating mutation identified initially in patients with sarcoidosis28 (another granulomatous disease) has also been seen in patients with other autoimmune diseases. This association may reflect linkage disequilibrium of the BTNL2 mutation with HLA-DQB1–HLA-DRB1 haplotypes that confer a predisposition to disease.29,30 Although strong linkage disequilibrium across this region obscures the identity of the causal alleles underpinning the associations with primary biliary cirrhosis, haplotype analyses (Table 1 in the Supplementary Appendix) suggest that most of the risk of primary biliary cirrhosis derives from two common haplotypes, AACA (P=1.09×10−10) and CACA (P=7.29×10−10), across the C6orf10, BTNL2, and HLA-DQB1 genes. By validating the MHC class II region as a major contributor to the risk of primary biliary cirrhosis, our data support further dissection of this region.
HLA contributions to the risk of primary biliary cirrhosis are proportionately less significant than the contributions to risks of other autoimmune diseases.31 The association of the HLA-DQB1 locus with the risk of primary biliary cirrhosis (odds ratio, 1.75) is similar to the associations of IL12A (odds ratio, 1.54) and IL12RB2 (odds ratio, 1.51). In addition, the population attributable fraction for the IL12A rs6441286 GT and GG risk genotypes (21.5%) is slightly higher than that for HLA-DQB1 rs2856683 CC and CA risk genotypes (21.2%) (Table 11 in the Supplementary Appendix). The IL12RB2 locus also provides a high population attributable fraction, 18.4%. These estimates suggest substantive contributions of all three loci to the risk of primary biliary cirrhosis.
Our data suggest important contributions of the IL12A and IL12RB2 loci to susceptibility to primary biliary cirrhosis. This possibility is consistent with the major immunoregulatory roles of the protein products, interleukin-12 p35 and interleukin-12 receptor β2, which associate with the interleukin-12 p40 and interleukin-12 receptor β1 chains, respectively, to generate interleukin-12 and its receptor. The binding of interleukin-12 to its receptor is thought to modulate autoimmune responses by evoking interferon-γ production, which may in turn inhibit interleukin-23–driven induction of interleukin-17–producing helper T lymphocytes.32,33 The relevance of this pathway to primary biliary cirrhosis is suggested by our finding of associations between primary biliary cirrhosis and several SNPs across the STAT4 gene, which encodes an effector that is integral to interleukin-12 signaling. The SNP rs7574865 in STAT4 intron 3 is known to be associated with risks of rheumatoid arthritis, systemic lupus erythematosus,22 and type 1 diabetes34; our findings suggest that it is associated with primary biliary cirrhosis as well (P=1.21×10−3; odds ratio, 1.31) (Table 6 in the Supplementary Appendix), although the strongest signals of association at this locus came from intronic SNPs outside the linkage-disequilibrium block tagged by rs7574865.
Similarly, another SNP associated with primary biliary cirrhosis, rs178105416 in the IL12A gene, has previously been shown to be associated with the risk of celiac disease,35 whereas SNPs in the genes encoding interleukin-12β and the interleukin-23 receptor (key components of the signaling pathway of interleukin-12 and its receptor and the related interleukin-23 immunomodulatory axis) are associated with risks for psoriasis and inflammatory bowel disease, although not primary biliary cirrhosis.25,26,36
Our genomewide association study had a statistical power of 82% to detect associations with an odds ratio of 1.5 for patients as compared with controls (see the Supplementary Appendix) and thus provides strong evidence for associations of primary biliary cirrhosis with HLA, IL12A, and IL12RB2 variants. However, the lower statistical power of the study to detect associations with more modest effects, even in the combined analysis (e.g., estimated power of 60% to detect associations with an odds ratio of 1.4) may have impeded the discovery of some risk alleles for primary biliary cirrhosis. Analyses of data from larger and prospectively followed groups of subjects will be required to identify other non-HLA loci influencing risk and to elucidate the relevance of the loci associated with primary biliary cirrhosis to clinically important subphenotypes such as disease progression. Population stratification appeared to have a minimal effect in our analysis, given the minimal inflation of the genomewide chi-square statistics and the similar levels of association in the analysis that was restricted to Canadian subjects.
The causal alleles at the identified risk loci remain unknown. The strongest associations at the IL12A and IL12RB2 loci are with SNPs in the downstream and intronic regions, suggesting that these variants may influence IL12A–IL12RB2 expression. Although it requires further investigation, this possibility is consistent with the development of autoimmune and lymphoproliferative disease in IL12RB2 knockout mice37 and a recent report describing the development of biliary cirrhosis in a child with interleukin-12 deficiency.38 These observations, as well as the cumulative data linking inherited deficiencies of interleukin-12, interleukin-12 receptor, and interferon-γ to increased susceptibility to and severity of mycobacterial and other infectious diseases,39 raise the intriguing possibility that IL12A and IL12RB2 variants associated with primary biliary cirrhosis engender both an impaired response to infection and a potentiated risk of autoimmunity, the former possibly driving the latter.
Precise characterization of the nature and functional sequelae of the HLA and IL12A–IL12RB2 variants that confer a risk of primary biliary cirrhosis remains to be achieved. The association of primary biliary cirrhosis with variants at these loci confirms the critical role of immunogenetic factors in the genesis of this disease. These data point to the possibility that modulation of signaling by interleukin-12 and its receptor may be beneficial in the treatment of patients with primary biliary cirrhosis.
Supported by grants from the Canadian Institutes for Health Research (MOP 74621), the Ontario Research Fund (RE01-061), the Canadian Primary Biliary Cirrhosis Society, the U.S. National Institutes of Health (K23 DK68290, RO3 DK78527, and RO1 DK80670), the American Gastroenterological Association, and the A.J. and Sigismunda Palumbo Charitable Trust.
Dr. Hirschfield reports receiving fellowship support from the University of Cambridge Parke Davis Fund, the Canadian Commonwealth Association, and the Canadian Association for the Study of the Liver; and Dr. Mason, grant support from Novartis and Schering-Plough. Dr. Peltekian reports being chair of the Canadian Liver Foundation. Dr. Heathcote reports receiving lecture fees and grant support from Axcan Pharma; and Dr. Siminovitch, research support from the Immunogenomics Program of the McLaughlin Centre for Molecular Medicine, from a Canada Research Chair award, and from the Sherman Family Foundation. No other potential conflict of interest relevant to this article was reported.
Drs. Hirschfield and Liu contributed equally to this article.
This article (10.1056/NEJMoa0810440) was published on May 20, 2009, at NEJM.org.
We thank all the study subjects and the technical staff of the University Health Network Analytical Genetics Technology Centre for their assistance in this research.
Source Information
From the University of Toronto (G.M.H., X.L., C.X., G.X., Yan Lu, E.J.W., E.J.H., K.A.S.) and Liver Center, Toronto Western Hospital (G.M.H., C.C., E.J.H.) — both in Toronto; University of Alberta, Edmonton (A.L.M.); University of Calgary, Calgary, AB (R.P.M.); Dalhousie University, Halifax, NS (K.M.P.); and London Health Sciences Centre, London, ON (C.N.G.) — all in Canada; M.D. Anderson Cancer Center, Houston (Yue Lu, X.G., K.J., C.I.A.); and Mayo Clinic College of Medicine, Rochester, MN (B.D.J., E.J.A., K.N.L.).
Address reprint requests to Dr. Siminovitch at Mount Sinai Hospital, 600 University Ave., Room 778D, Toronto, ON M5G 1X5, Canada, or at ksimin@mshri.on.ca.
- References
References
1
Kaplan MM ,Gershwin ME . Primary biliary cirrhosis. N Engl J Med 2005;353:1261-1273[Erratum, N Engl J Med 2006;354:313.]
Full Text | Web of Science | Medline2
Poupon RE ,Poupon R ,Balkau B . Ursodiol for the long-term treatment of primary biliary cirrhosis. N Engl J Med 1994;330:1342-1347
Full Text | Web of Science | Medline3
Gershwin ME ,Mackay IR . The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology 2008;47:737-745
CrossRef | Web of Science | Medline4
Irie J ,Wu Y ,Wicker LS , et al. NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med 2006;203:1209-1219
CrossRef | Web of Science | Medline5
Oertelt S ,Lian ZX ,Cheng CM , et al. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol 2006;177:1655-1660
Web of Science | Medline6
Wakabayashi K ,Lian ZX ,Moritoki Y , et al. IL-2 receptor alpha(−/−) mice and the development of primary biliary cirrhosis. Hepatology 2006;44:1240-1249
CrossRef | Web of Science | Medline7
Selmi C ,Mayo MJ ,Bach N , et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 2004;127:485-492
CrossRef | Web of Science | Medline8
Jones DE ,Watt FE ,Metcalf JV ,Bassendine MF ,James OF . Familial primary biliary cirrhosis reassessed: a geographically-based population study. J Hepatol 1999;30:402-407
CrossRef | Web of Science | Medline9
Watt FE ,James OF ,Jones DE . Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study. QJM 2004;97:397-406
CrossRef | Medline10
Lazaridis KN ,Juran BD ,Boe GM , et al. Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis. Hepatology 2007;46:785-792
CrossRef | Web of Science | Medline11
Donaldson PT ,Baragiotta A ,Heneghan MA , et al. HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: a large-scale study. Hepatology 2006;44:667-674
CrossRef | Web of Science | Medline12
Invernizzi P ,Selmi C ,Poli F , et al. Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: a multicenter study of 664 patients and 1992 healthy controls. Hepatology 2008;48:1906-1912
CrossRef | Web of Science | Medline13
Donaldson P ,Veeramani S ,Baragiotta A , et al. Cytotoxic T-lymphocyte-associated antigen-4 single nucleotide polymorphisms and haplotypes in primary biliary cirrhosis. Clin Gastroenterol Hepatol 2007;5:755-760
CrossRef | Web of Science | Medline14
Juran BD ,Atkinson EJ ,Schlicht EM ,Fridley BL ,Lazaridis KN . Primary biliary cirrhosis is associated with a genetic variant in the 3' flanking region of the CTLA4 gene. Gastroenterology 2008;135:1200-1206
CrossRef | Web of Science | Medline15
Walker EJ ,Hirschfield GM ,Xu C , et al. CTLA-4/ICOS gene variants and haplotypes are associated with rheumatoid arthritis and primary biliary cirrhosis in the Canadian population. Arthritis Rheum 2009;60:931-937
CrossRef | Web of Science | Medline16
Heathcote EJ . Management of primary biliary cirrhosis: the American Association for the Study of Liver Diseases practice guidelines. Hepatology 2000;31:1005-1013
CrossRef | Web of Science | Medline17
Amos CI ,Wu X ,Broderick P , et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 2008;40:616-622
CrossRef | Web of Science | Medline18
Purcell S ,Neale B ,Todd-Brown K , et al. PLINK: a tool set for whole-genome association and population-based linkage analysis. Am J Hum Genet 2007;81:559-575
CrossRef | Web of Science | Medline19
Price AL ,Patterson NJ ,Plenge RM ,Weinblatt ME ,Shadick NA ,Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006;38:904-909
CrossRef | Web of Science | Medline20
Gabriel SB ,Schaffner SF ,Nguyen H , et al. The structure of haplotype blocks in the human genome. Science 2002;296:2225-2229
CrossRef | Web of Science | Medline21
Wellcome Trust Case Control Consortium
CrossRef | Web of Science | Medline22
Remmers EF ,Plenge RM ,Lee AT , et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007;357:977-986
Full Text | Web of Science | Medline23
Sigurdsson S ,Nordmark G ,Goring HH , et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 2005;76:528-537
CrossRef | Web of Science | Medline24
Dideberg V ,Kristjansdottir G ,Milani L , et al. An insertion-deletion polymorphism in the interferon regulatory factor 5 (IRF5) gene confers risk of inflammatory bowel diseases. Hum Mol Genet 2007;16:3008-3016
CrossRef | Web of Science | Medline25
Duerr RH ,Taylor KD ,Brant SR , et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006;314:1461-1463
CrossRef | Web of Science | Medline26
Cargill M ,Schrodi SJ ,Chang M , et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 2007;80:273-290
CrossRef | Web of Science | Medline27
Invernizzi P ,Selmi C ,Mackay IR ,Podda M ,Gershwin ME . From bases to basis: linking genetics to causation in primary biliary cirrhosis. Clin Gastroenterol Hepatol 2005;3:401-410
CrossRef | Web of Science | Medline28
Valentonyte R ,Hampe J ,Huse K , et al. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet 2005;37:357-364[Erratum, Nat Genet 2005;37:652.]
CrossRef | Web of Science | Medline29
Traherne JA ,Barcellos LF ,Sawcer SJ , et al. Association of the truncating splice site mutation in BTNL2 with multiple sclerosis is secondary to HLA-DRB1*15. Hum Mol Genet 2006;15:155-161
CrossRef | Web of Science | Medline30
Mochida A ,Kinouchi Y ,Negoro K , et al. Butyrophilin-like 2 gene is associated with ulcerative colitis in the Japanese under strong linkage disequilibrium with HLA-DRB1*1502. Tissue Antigens 2007;70:128-135
CrossRef | Web of Science | Medline31
Todd JA ,Walker NM ,Cooper JD , et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 2007;39:857-864
CrossRef | Web of Science | Medline32
Goriely S ,Neurath MF ,Goldman M . How microorganisms tip the balance between interleukin-12 family members. Nat Rev Immunol 2008;8:81-86
CrossRef | Web of Science | Medline33
Hoeve MA ,Savage ND ,de Boer T , et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol 2006;36:661-670
CrossRef | Web of Science | Medline34
Fung EY ,Smyth DJ ,Howson JM , et al. Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun 2009;10:188-191
CrossRef | Web of Science | Medline35
Hunt KA ,Zhernakova A ,Turner G , et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 2008;40:395-402
CrossRef | Web of Science | Medline36
Fisher SA ,Tremelling M ,Anderson CA , et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet 2008;40:710-712
CrossRef | Web of Science | Medline37
Airoldi I ,Di Carlo E ,Cocco C , et al. Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy. Blood 2005;106:3846-3853
CrossRef | Web of Science | Medline38
Pulickal AS ,Hambleton S ,Callaghan MJ , et al. Biliary cirrhosis in a child with inherited interleukin-12 deficiency. J Trop Pediatr 2008;54:269-271
CrossRef | Web of Science | Medline39
Filipe-Santos O ,Bustamante J ,Chapgier A , et al. Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features. Semin Immunol 2006;18:347-361[Erratum, Semin Immunol 2007;19:136-7.]
CrossRef | Web of Science | Medline
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1
Lauren W Collison, Greg M Delgoffe, Clifford S Guy, Kate M Vignali, Vandana Chaturvedi, DeLisa Fairweather, Abhay R Satoskar, K Christopher Garcia, Christopher A Hunter, Charles G Drake, Peter J Murray, Dario A A Vignali. (2012) The composition and signaling of the IL-35 receptor are unconventional. Nature Immunology
CrossRef2
G M Hirschfield, G Xie, E Lu, Y Sun, B D Juran, V Chellappa, C Coltescu, A L Mason, P Milkiewicz, R P Myers, J A Odin, V A Luketic, B Bacon, H Bodenheimer, V Liakina, C Vincent, C Levy, S Pillai, K N Lazaridis, C I Amos, K A Siminovitch. (2012) Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes. Genes and Immunity
CrossRef3
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CrossRef4
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CrossRef5
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CrossRef6
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CrossRef7
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CrossRef8
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CrossRef9
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CrossRef10
Ulrich Beuers, Keith D. Lindor. (2011) A major step towards effective treatment evaluation in primary biliary cirrhosis. Journal of Hepatology 55:6, 1178-1180
CrossRef11
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CrossRef12
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CrossRef13
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CrossRef14
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CrossRef15
Gideon M. Hirschfield. (2011) Diagnosis of primary biliary cirrhosis. Best Practice & Research Clinical Gastroenterology 25:6, 701-712
CrossRef16
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CrossRef17
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CrossRef18
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CrossRef19
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CrossRef20
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CrossRef21
David E.J. Jones. (2011) A potential retroviral aetiology for mouse PBC: More answers or more questions?. Journal of Hepatology 55:4, 750-752
CrossRef22
Ana Lleo, M. Eric Gershwin, Alberto Mantovani, Pietro Invernizzi. (2011) Towards common denominators in primary biliary cirrhosis: The role of IL-12. Journal of Hepatology
CrossRef23
Daniel S. Smyk, Maria G. Mytilinaiou, Piotr Milkiewicz, Eirini I. Rigopoulou, Pietro Invernizzi, Dimitrios P. Bogdanos. (2011) Towards systemic sclerosis and away from primary biliary cirrhosis: the case of PTPN22. Autoimmunity Highlights
CrossRef24
Daniel S. Smyk, Dimitrios P. Bogdanos, Stephen Kriese, Charalambos Billinis, Andrew K. Burroughs, Eirini I. Rigopoulou. (2011) Urinary tract infection as a risk factor for autoimmune liver disease: From bench to bedside. Clinics and Research in Hepatology and Gastroenterology
CrossRef25
T R O'Brien, I Kohaar, R M Pfeiffer, D Maeder, M Yeager, E E Schadt, L Prokunina-Olsson. (2011) Risk alleles for chronic hepatitis B are associated with decreased mRNA expression of HLA-DPA1 and HLA-DPB1 in normal human liver. Genes and Immunity 12:6, 428-433
CrossRef26
Nelson Chuang, Rebekah G Gross, Joseph A Odin. (2011) Update on the epidemiology of primary biliary cirrhosis. Expert Review of Gastroenterology & Hepatology 5:5, 583-590
CrossRef27
Pietro Invernizzi. (2011) Human leukocyte antigen in primary biliary cirrhosis: An old story now reviving. Hepatology 54:2, 714-723
CrossRef28
Peter A. Berg. (2011) The role of the innate immune recognition system in the pathogenesis of primary biliary cirrhosis: a conceptual view. Liver International 31:7, 920-931
CrossRef29
Guanghua Rong, Renqian Zhong, Ana Lleo, Patrick S.C. Leung, Christopher L. Bowlus, Guo-Xiang Yang, Chen-Yen Yang, Ross L. Coppel, Aftab A. Ansari, Dean A. Cuebas, Howard J. Worman, Pietro Invernizzi, Gregory J. Gores, Gary Norman, Xiao-Song He, M. Eric Gershwin. (2011) Epithelial cell specificity and apotope recognition by serum autoantibodies in primary biliary cirrhosis. Hepatology 54:1, 196-203
CrossRef30
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CrossRef31
A. Tanaka, P. Invernizzi, H. Ohira, K. Kikuchi, S. Nezu, R. Kosoy, M. F. Seldin, M. E. Gershwin, H. Takikawa. (2011) Replicated association of 17q12-21 with susceptibility of primary biliary cirrhosis in a Japanese cohort. Tissue Antigens 78:1, 65-68
CrossRef32
Deepak Garg, Arpit Nagar, Shaile Philips, Naoki Takahashi, Srinivasa R. Prasad, Alampady K. Shanbhogue, Dushyant V. Sahani. (2011) Immunological diseases of the pancreatico-hepatobiliary system: update on etiopathogenesis and cross-sectional imaging findings. Abdominal Imaging
CrossRef33
Carlo Selmi, Christopher L Bowlus, M Eric Gershwin, Ross L Coppel. (2011) Primary biliary cirrhosis. The Lancet 377:9777, 1600-1609
CrossRef34
Vincent Zimmer, Frank Lammert. (2011) Genetics in liver disease: new concepts. Current Opinion in Gastroenterology 27:3, 231-239
CrossRef35
, Tatsuo Inamine, Minoru Nakamura, Ayumi Kawauchi, Yayoi Shirakawa, Hisae Hashiguchi, Yoshihiro Aiba, Akinobu Taketomi, Ken Shirabe, Makoto Nakamuta, Shigeki Hayashi, Takeo Saoshiro, Atsumasa Komori, Hiroshi Yatsuhashi, Shinji Kondo, Katsuhisa Omagari, Yoshihiko Maehara, Hiromi Ishibashi, Kazuhiro Tsukamoto. (2011) A polymorphism in the integrin αV subunit gene affects the progression of primary biliary cirrhosis in Japanese patients. Journal of Gastroenterology 46:5, 676-686
CrossRef36
Susanne N. Weber, Frank Lammert. (2011) Genetics of Liver Injury and Fibrosis. Alcoholism: Clinical and Experimental Research 35:5, 800-803
CrossRef37
Qing Lan, Sophia S. Wang, Idan Menashe, Bruce Armstrong, Yawei Zhang, Patricia Hartge, Mark P. Purdue, Theodore R. Holford, Lindsay M. Morton, Anne Kricker, James R. Cerhan, Andrew Grulich, Wendy Cozen, Shelia H. Zahm, Meredith Yeager, Claire M. Vajdic, Maryjean Schenk, Brian Leaderer, Jeff Yuenger, Richard K. Severson, Nilanjan Chatterjee, Stephen J. Chanock, Tongzhang Zheng, Nathaniel Rothman. (2011) Genetic variation in Th1/Th2 pathway genes and risk of non-Hodgkin lymphoma: a pooled analysis of three population-based case-control studies. British Journal of Haematology 153:3, 341-350
CrossRef38
Judy H. Cho, Steven R. Brant. (2011) Recent Insights Into the Genetics of Inflammatory Bowel Disease. Gastroenterology 140:6, 1704-1712.e2
CrossRef39
Margaret F. Bassendine. 2011. Primary Biliary Cirrhosis. , 329-341.
CrossRef40
Ann K Daly, Stefano Ballestri, Lucia Carulli, Paola Loria, Christopher P Day. (2011) Genetic determinants of susceptibility and severity in nonalcoholic fatty liver disease. Expert Review of Gastroenterology & Hepatology 5:2, 253-263
CrossRef41
Vincent Zimmer, Frank Lammert. (2011) Genetics and epigenetics in the fibrogenic evolution of chronic liver diseases. Best Practice & Research Clinical Gastroenterology 25:2, 269-280
CrossRef42
Qiang Huang, Feng Shao, Cheng Wang, Lu-jun Qiu, Yuan-guo Hu, Ji-hai Yu. (2011) Association between CTLA-4 Exon-1 +49A>G Polymorphism and Primary Biliary Cirrhosis Risk: A Meta-analysis. Archives of Medical Research 42:3, 235-238
CrossRef43
George F Mells, James A B Floyd, Katherine I Morley, Heather J Cordell, Christopher S Franklin, So-Youn Shin, Michael A Heneghan, James M Neuberger, Peter T Donaldson, Darren B Day, Samantha J Ducker, Agnes W Muriithi, Elizabeth F Wheater, Christopher J Hammond, Muhammad F Dawwas, David E Jones, Leena Peltonen, Graeme J Alexander, Richard N Sandford, Carl A Anderson. (2011) Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nature Genetics 43:4, 329-332
CrossRef44
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CrossRef45
W. Stremmel, K.H. Weiss, D. Gotthardt, W. Gilles, U. Merle. (2011) Molekulare Diagnostik bei genetischen Lebererkrankungen. Der Gastroenterologe 6:2, 92-97
CrossRef46
A. Tanaka, H. Ohira, K. Kikuchi, S. Nezu, A. Shibuya, I. Bianchi, M. Podda, P. Invernizzi, H. Takikawa. (2011) Genetic association of Fc receptor-like 3 polymorphisms with susceptibility to primary biliary cirrhosis: ethnic comparative study in Japanese and Italian patients. Tissue Antigens 77:3, 239-243
CrossRef47
Daniel Smyk, Eirini I. Rigopoulou, Harold Baum, Andrew K. Burroughs, Diego Vergani, Dimitrios P. Bogdanos. (2011) Autoimmunity and Environment: Am I at risk?. Clinical Reviews in Allergy & Immunology
CrossRef48
Yasuhiro Miyake, Fusao Ikeda, Akinobu Takaki, Kazuhiro Nouso, Kazuhide Yamamoto. (2011) +49A/G polymorphism of cytotoxic T-lymphocyte antigen 4 gene in type 1 autoimmune hepatitis and primary biliary cirrhosis: A meta-analysis. Hepatology Research 41:2, 151-159
CrossRef49
Shuying S. Li, Hongwei Wang, Anajane Smith, Bo Zhang, Xinyi Cindy Zhang, Gary Schoch, Daniel Geraghty, John A. Hansen, Lue Ping Zhao. (2011) Predicting multiallelic genes using unphased and flanking single nucleotide polymorphisms. Genetic Epidemiology 35:2, 85-92
CrossRef50
Marco Folci, Francesca Meda, M. Eric Gershwin, Carlo Selmi. (2011) Cutting-Edge Issues in Primary Biliary Cirrhosis. Clinical Reviews in Allergy & Immunology
CrossRef51
David E. J. Jones, George Mells. (2011) The genetics of primary biliary cirrhosis: The revolution moves on. Hepatology 53:1, 362-364
CrossRef52
Carlo Selmi, Ian R Mackay, M Eric Gershwin. (2011) The autoimmunity of primary biliary cirrhosis and the clonal selection theory. Immunology and Cell Biology 89:1, 70-80
CrossRef53
Fumi K Varyani, Joe West, Timothy R Card. (2011) An increased risk of urinary tract infection precedes development of primary biliary cirrhosis. BMC Gastroenterology 11:1, 95
CrossRef54
Cristina Rigamonti, Dimitrios P. Bogdanos, Maria G. Mytilinaiou, Daniel S. Smyk, Eirini I. Rigopoulou, Andrew K. Burroughs. (2011) Primary Biliary Cirrhosis Associated with Systemic Sclerosis: Diagnostic and Clinical Challenges. International Journal of Rheumatology 2011, 1-12
CrossRef55
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CrossRef56
Juan F. Medina. (2011) Role of the Anion Exchanger 2 in the Pathogenesis and Treatment of Primary Biliary Cirrhosis. Digestive Diseases 29:1, 103-112
CrossRef57
Roman Müllenbach, Frank Lammert. (2011) An Update on Genetic Analysis of Cholestatic Liver Diseases: Digging Deeper. Digestive Diseases 29:1, 72-77
CrossRef58
Espen Melum, Andre Franke, Christoph Schramm, Tobias J Weismüller, Daniel Nils Gotthardt, Felix A Offner, Brian D Juran, Jon K Laerdahl, Verena Labi, Einar Björnsson, Rinse K Weersma, Liesbet Henckaerts, Andreas Teufel, Christian Rust, Eva Ellinghaus, Tobias Balschun, Kirsten Muri Boberg, David Ellinghaus, Annika Bergquist, Peter Sauer, Euijung Ryu, Johannes Roksund Hov, Jochen Wedemeyer, Björn Lindkvist, Michael Wittig, Robert J Porte, Kristian Holm, Christian Gieger, H-Erich Wichmann, Pieter Stokkers, Cyriel Y Ponsioen, Heiko Runz, Adolf Stiehl, Cisca Wijmenga, Martina Sterneck, Severine Vermeire, Ulrich Beuers, Andreas Villunger, Erik Schrumpf, Konstantinos N Lazaridis, Michael P Manns, Stefan Schreiber, Tom H Karlsen. (2011) Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci. Nature Genetics 43:1, 17-19
CrossRef59
Hiromi Ishibashi, Atsumasa Komori, Shinji Shimoda, Yoko M. Ambrosini, M. Eric Gershwin, Minoru Nakamura. (2011) Risk Factors and Prediction of Long-term Outcome in Primary Biliary Cirrhosis. Internal Medicine 50:1, 1-10
CrossRef60
Hironobu Saito, Atsushi Takahashi, Kazumichi Abe, Kyoko Monoe, Yukiko Kanno, Junko Yokokawa, Hiromasa Ohira. (2011) Two cases of primary biliary cirrhosis associated with systemic lupus erythematosus. Kanzo 52:3, 169-175
CrossRef61
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CrossRef62
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CrossRef63
Takeji Umemura, Satoru Joshita, Tetsuya Ichijo, Kaname Yoshizawa, Yoshihiko Katsuyama, Eiji Tanaka, Masao Ota, . (2011) Human leukocyte antigen class II molecules confer both susceptibility and progression in japanese patients with primary biliary cirrhosis. Hepatologyn/a-n/a
CrossRef64
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CrossRef65
Robert J. Clifford, Jinghui Zhang, Daoud M. Meerzaman, Myung-Soo Lyu, Ying Hu, Constance M. Cultraro, Richard P. Finney, Jenny M. Kelley, Sol Efroni, Sharon I. Greenblum, Cu V. Nguyen, William L. Rowe, Sweta Sharma, Gang Wu, Chunhua Yan, Hongen Zhang, Young-Hwa Chung, Jeong A. Kim, Neung Hwa Park, Il Han Song, Kenneth H. Buetow. (2010) Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma. Hepatology 52:6, 2034-2043
CrossRef66
Marcin Krawczyk, Roman Müllenbach, Susanne N. Weber, Vincent Zimmer, Frank Lammert. (2010) Genome-wide association studies and genetic risk assessment of liver diseases. Nature Reviews Gastroenterology & Hepatology 7:12, 669-681
CrossRef67
Jay H. Lefkowitch. (2010) Advances in Hepatobiliary Pathology: Update for 2010. Clinics in Liver Disease 14:4, 747-762
CrossRef68
Masanobu Tsuda, Troy R. Torgerson, Carlo Selmi, Eleonora Gambineri, Magda Carneiro-Sampaio, Sara Ciullini Mannurita, Patrick S.C. Leung, Gary L. Norman, M. Eric Gershwin. (2010) The spectrum of autoantibodies in IPEX syndrome is broad and includes anti-mitochondrial autoantibodies. Journal of Autoimmunity 35:3, 265-268
CrossRef69
Gideon M. Hirschfield, E. Jenny Heathcote, M. Eric Gershwin. (2010) Pathogenesis of Cholestatic Liver Disease and Therapeutic Approaches. Gastroenterology 139:5, 1481-1496
CrossRef70
Brian D. Juran, Konstantinos N. Lazaridis. (2010) Update on the genetics and genomics of PBC. Journal of Autoimmunity 35:3, 181-187
CrossRef71
O. A. Panagiotou, E. Evangelou, J. P. A. Ioannidis. (2010) Genome-wide Significant Associations for Variants With Minor Allele Frequency of 5% or Less--An Overview: A HuGE Review. American Journal of Epidemiology 172:8, 869-889
CrossRef72
Douglas L. Nguyen, Brian D. Juran, Konstantinos N. Lazaridis. (2010) Primary biliary cirrhosis. Best Practice & Research Clinical Gastroenterology 24:5, 647-654
CrossRef73
Gideon M Hirschfield, E Jenny Heathcote. 2010. Primary Biliary Cirrhosis. , 508-523.
CrossRef74
Ana Lleo, Christopher L. Bowlus, Guo-Xiang Yang, Pietro Invernizzi, Mauro Podda, Judy Van de Water, Aftab A. Ansari, Ross L. Coppel, Howard J. Worman, Gregory J. Gores, M. Eric Gershwin. (2010) Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis. Hepatology 52:3, 987-998
CrossRef75
Satoru Joshita, Takeji Umemura, Kaname Yoshizawa, Yoshihiko Katsuyama, Eiji Tanaka, Minoru Nakamura, Hiromi Ishibashi, Masao Ota. (2010) Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients. Journal of Hepatology 53:3, 537-541
CrossRef76
Rajpreet K. Arora-Singh, Shervin Assassi, Deborah J. del Junco, Frank C. Arnett, Marilyn Perry, Uzma Irfan, Roozbeh Sharif, Tony Mattar, Maureen D. Mayes. (2010) Autoimmune diseases and autoantibodies in the first degree relatives of patients with systemic sclerosis. Journal of Autoimmunity 35:1, 52-57
CrossRef77
Gideon M Hirschfield, Xiangdong Liu, Younghun Han, Ivan P Gorlov, Yan Lu, Chun Xu, Yue Lu, Wei Chen, Brian D Juran, Catalina Coltescu, Andrew L Mason, Piotr Milkiewicz, Robert P Myers, Joseph A Odin, Velimir A Luketic, Danute Speiciene, Catherine Vincent, Cynthia Levy, Peter K Gregersen, Jinyi Zhang, E Jenny Heathcote, Konstantinos N Lazaridis, Christopher I Amos, Katherine A Siminovitch. (2010) Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nature Genetics 42:8, 655-657
CrossRef78
Xiangdong Liu, Pietro Invernizzi, Yue Lu, Roman Kosoy, Yan Lu, Ilaria Bianchi, Mauro Podda, Chun Xu, Gang Xie, Fabio Macciardi, Carlo Selmi, Sara Lupoli, Russell Shigeta, Michael Ransom, Ana Lleo, Annette T Lee, Andrew L Mason, Robert P Myers, Kevork M Peltekian, Cameron N Ghent, Francesca Bernuzzi, Massimo Zuin, Floriano Rosina, Elisabetta Borghesio, Annarosa Floreani, Roberta Lazzari, Grazia Niro, Angelo Andriulli, Luigi Muratori, Paolo Muratori, Piero L Almasio, Pietro Andreone, Marzia Margotti, Maurizia Brunetto, Barbara Coco, Domenico Alvaro, Maria C Bragazzi, Fabio Marra, Alessandro Pisano, Cristina Rigamonti, Massimo Colombo, Marco Marzioni, Antonio Benedetti, Luca Fabris, Mario Strazzabosco, Piero Portincasa, Vincenzo O Palmieri, Claudio Tiribelli, Lory Croce, Savino Bruno, Sonia Rossi, Maria Vinci, Cleofe Prisco, Alberto Mattalia, Pierluigi Toniutto, Antonio Picciotto, Andrea Galli, Carlo Ferrari, Silvia Colombo, Giovanni Casella, Lorenzo Morini, Nicola Caporaso, Agostino Colli, Giancarlo Spinzi, Renzo Montanari, Peter K Gregersen, E Jenny Heathcote, Gideon M Hirschfield, Katherine A Siminovitch, Christopher I Amos, M Eric Gershwin, Michael F Seldin. (2010) Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nature Genetics 42:8, 658-660
CrossRef79
Nobuhisa Mizuki, Akira Meguro, Masao Ota, Shigeaki Ohno, Tomoko Shiota, Tatsukata Kawagoe, Norihiko Ito, Jiro Kera, Eiichi Okada, Keisuke Yatsu, Yeong-Wook Song, Eun-Bong Lee, Nobuyoshi Kitaichi, Kenichi Namba, Yukihiro Horie, Mitsuhiro Takeno, Sunao Sugita, Manabu Mochizuki, Seiamak Bahram, Yoshiaki Ishigatsubo, Hidetoshi Inoko. (2010) Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet's disease susceptibility loci. Nature Genetics 42:8, 703-706
CrossRef80
Brian D. Juran, Elizabeth J. Atkinson, Joseph J. Larson, Erik M. Schlicht, Xiangdong Liu, E. Jenny Heathcote, Gideon M. Hirschfield, Katherine A. Siminovitch, Konstantinos N. Lazaridis. (2010) Carriage of a tumor necrosis factor polymorphism amplifies the cytotoxic T-lymphocyte antigen 4 attributed risk of primary biliary cirrhosis: Evidence for a gene-gene interaction. Hepatology 52:1, 223-229
CrossRef81
Marina G. Silveira, Elizabeth M. Brunt, Jenny Heathcote, Gregory J. Gores, Keith D. Lindor, Marlyn J. Mayo. (2010) American association for the study of liver diseases endpoints conference: Design and endpoints for clinical trials in primary biliary cirrhosis. Hepatology 52:1, 349-359
CrossRef82
Arthur Kaser, Eduardo Martínez-Naves, Richard S Blumberg. (2010) Endoplasmic reticulum stress: implications for inflammatory bowel disease pathogenesis. Current Opinion in Gastroenterology 26:4, 318-326
CrossRef83
Christophe Corpechot, Yves Chrétien, Olivier Chazouillères, Raoul Poupon. (2010) Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. Journal of Hepatology 53:1, 162-169
CrossRef84
(2010) IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci. Genes and Immunity 11:5, 397-405
CrossRef85
Aldo J. Montano-Loza, Shawn Wasilenko, Jasper Bintner, Andrew L. Mason. (2010) Cyclosporine A inhibits in vitro replication of betaretrovirus associated with primary biliary cirrhosis. Liver International 30:6, 871-877
CrossRef86
Pietro Invernizzi, Carlo Selmi, M. Eric Gershwin. (2010) Update on primary biliary cirrhosis. Digestive and Liver Disease 42:6, 401-408
CrossRef87
Yoshiyuki Ueno, Yoko M Ambrosini, Yuki Moritoki, William M Ridgway, M Eric Gershwin. (2010) Murine models of autoimmune cholangitis. Current Opinion in Gastroenterology 26:3, 274-279
CrossRef88
Satoru Joshita, Takeji Umemura, Kaname Yoshizawa, Yoshihiko Katsuyama, Eiji Tanaka, Masao Ota. (2010) A2BP1 as a novel susceptible gene for primary biliary cirrhosis in Japanese patients. Human Immunology 71:5, 520-524
CrossRef89
Minoru Nakamura, Michio Yasunami, Hisayoshi Kondo, Hitomi Horie, Yoshihiro Aiba, Atsumasa Komori, Kiyoshi Migita, Hiroshi Yatsuhashi, Masahiro Ito, Shinji Shimoda, Hiromi Ishibashi, . (2010) Analysis of HLA-DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC): The HLA-DRB1polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC. Hepatology Research 40:5, 494-504
CrossRef90
Tom H. Karlsen, Espen Melum, Andre Franke. (2010) The utility of genome-wide association studies in hepatology. Hepatology 51:5, 1833-1842
CrossRef91
Raoul Poupon. (2010) Primary biliary cirrhosis: A 2010 update. Journal of Hepatology 52:5, 745-758
CrossRef92
Tom H Karlsen, Johannes R Hov. (2010) Genetics of cholestatic liver disease in 2010. Current Opinion in Gastroenterology 26:3, 251-258
CrossRef93
A. J. Montano-Loza, S. Wasilenko, J. Bintner, A. L. Mason. (2010) Cyclosporine A Protects Against Primary Biliary Cirrhosis Recurrence After Liver Transplantation. American Journal of Transplantation 10:4, 852-858
CrossRef94
Dermot P B McGovern, Agnès Gardet, Leif Törkvist, Philippe Goyette, Jonah Essers, Kent D Taylor, Benjamin M Neale, Rick T H Ong, Caroline Lagacé, Chun Li, Todd Green, Christine R Stevens, Claudine Beauchamp, Phillip R Fleshner, Marie Carlson, Mauro D'Amato, Jonas Halfvarson, Martin L Hibberd, Mikael Lördal, Leonid Padyukov, Angelo Andriulli, Elisabetta Colombo, Anna Latiano, Orazio Palmieri, Edmond-Jean Bernard, Colette Deslandres, Daan W Hommes, Dirk J de Jong, Pieter C Stokkers, Rinse K Weersma, Yashoda Sharma, Mark S Silverberg, Judy H Cho, Jing Wu, Kathryn Roeder, Steven R Brant, L Phillip Schumm, Richard H Duerr, Marla C Dubinsky, Nicole L Glazer, Talin Haritunians, Andy Ippoliti, Gil Y Melmed, David S Siscovick, Eric A Vasiliauskas, Stephan R Targan, Vito Annese, Cisca Wijmenga, Sven Pettersson, Jerome I Rotter, Ramnik J Xavier, Mark J Daly, John D Rioux, Mark Seielstad. (2010) Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nature Genetics 42:4, 332-337
CrossRef95
David K. Breslow, Sean R. Collins, Bernd Bodenmiller, Ruedi Aebersold, Kai Simons, Andrej Shevchenko, Christer S. Ejsing, Jonathan S. Weissman. (2010) Orm family proteins mediate sphingolipid homeostasis. Nature 463:7284, 1048-1053
CrossRef96
Motoko Sasaki, Yasuni Nakanuma. (2010) Biliary Epithelial Apoptosis, Autophagy, and Senescence in Primary Biliary Cirrhosis. Hepatitis Research and Treatment 2010, 1-10
CrossRef97
Gideon M. Hirschfield, Katherine A. Siminovitch. (2009) Toward the molecular dissection of primary biliary cirrhosis. Hepatology 50:5, 1347-1350
CrossRef98
Pietro Invernizzi, M. Eric Gershwin. (2009) The genetics of human autoimmune disease. Journal of Autoimmunity 33:3-4, 290-299
CrossRef99
Ian R. Mackay. (2009) Clustering and commonalities among autoimmune diseases. Journal of Autoimmunity 33:3-4, 170-177
CrossRef100
Jean-Charles Duclos-Vallee, Mylène Sebagh. (2009) Recurrence of autoimmune disease, primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis after liver transplantation. Liver Transplantation 15:S2, S25-S34
CrossRef101
Lisa Richards. (2009) Genetics: Genetic variants associated with primary biliary cirrhosis. Nature Reviews Gastroenterology & Hepatology 6:9, 502-502
CrossRef102
Simon Hohenester, Ronald P. J. Oude-Elferink, Ulrich Beuers. (2009) Primary biliary cirrhosis. Seminars in Immunopathology 31:3, 283-307
CrossRef103
Dominique J. Verlaan, Soizik Berlivet, Gary M. Hunninghake, Anne-Marie Madore, Mathieu Larivière, Sanny Moussette, Elin Grundberg, Tony Kwan, Manon Ouimet, Bing Ge, Rose Hoberman, Marcin Swiatek, Joana Dias, Kevin C.L. Lam, Vonda Koka, Eef Harmsen, Manuel Soto-Quiros, Lydiana Avila, Juan C. Celedón, Scott T. Weiss, Ken Dewar, Daniel Sinnett, Catherine Laprise, Benjamin A. Raby, Tomi Pastinen, Anna K. Naumova. (2009) Allele-Specific Chromatin Remodeling in the ZPBP2/GSDMB/ORMDL3 Locus Associated with the Risk of Asthma and Autoimmune Disease. The American Journal of Human Genetics 85:3, 377-393
CrossRef
