Alternative titles; symbols
SNOMEDCT: 1761006, 31712002; ICD10CM: K74.3; ORPHA: 186; DO: 0070358;
Cytogenetic location: 3q25.33 Genomic coordinates (GRCh38): 3:159,300,001-161,000,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q25.33 | Biliary cirrhosis, primary, 1 | 109720 | Autosomal dominant | 2 |
Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic liver disease that usually affects middle-aged women and eventually leads to liver failure (summary by Kaplan, 1996).
Genetic Heterogeneity of Primary Biliary Cirrhosis
Primary biliary cirrhosis-1 (PBC1) is significantly associated with SNPs at the IL12A locus (161560) on chromosome 3q25.33.
Significant association of PBC has also been shown with SNPs at the HLA-DQB1 locus (604305) on chromosome 6p21.3 (PBC2; 613007), at the IL12RB2 locus (601642) on chromosome 1p31.2 (PBC3; 613008), at the IRF5 (607218)-TNPO3 (610032) locus on chromosome 7q32 (PBC4; 614220), and at the ZPBP2 locus (608499) on chromosome 17q12-q21 (PBC5; 614221).
See also Reynolds syndrome (613471), in which primary biliary cirrhosis is a feature.
Jaup and Zettergren (1980) studied familial incidence of primary biliary cirrhosis. In the study of patients with PBC and their relatives, Miller et al. (1983) used a method based on the finding that the in vitro addition of concanavalin A to pokeweed mitogen-stimulated lymphocytes activates suppressor cells, which in turn inhibit immunoglobulin synthesis. Significant impairment of IgG suppression was observed in 13 of 16 patients with PBC and 6 of 23 healthy relatives; all 6 relatives were females. No abnormal suppression was found in unrelated household contacts, patients with other forms of cirrhosis, or healthy controls. They suggested that the finding is not a result of the PBC but a genetic marker of susceptibility to the disorder.
Hirakata et al. (1988) described 2 unrelated patients with a combination of the CREST syndrome (181750) and primary biliary cirrhosis.
Tsuji et al. (1992) studied 18 healthy first-degree relatives of patients with primary biliary cirrhosis in 2 families. In each of these 2 families, there were 2 persons with PBC: 2 sisters in one family and a brother and sister in the other.
Kaplan (1996) reviewed all aspects of primary biliary cirrhosis, including the genetics.
Coppel et al. (1988) identified a human cDNA clone encoding the complete amino acid sequence of the 70-kD autoantigen (DLAT; 608770) found in high frequency in the serum of patients with PBC.
By ELISA, Szostecki et al. (1990) found that 50 of 184 primary biliary cirrhosis patients had autoantibodies to SP100 (604585). They did not detect such autoantibodies in patients with other liver diseases and detected them only rarely in patients with polymyositis and mixed connective tissue disease.
Tsuji et al. (1992) reported findings suggesting that impairment of concanavalin A-inducible lymphocytes, mainly suppressor T cells, is one of the contributing factors in the development of PBC.
The amino terminus of the lamin B receptor (LBR; 600024) has been recognized by autoantibodies from patients with primary biliary cirrhosis (Courvalin et al., 1990, Ye and Worman, 1994).
Graham et al. (2000) found a significant increase in the prevalence of a specific allele at a microsatellite region in the promoter region of the NRAMP1 gene (600266) in patients with PBC as compared to normal controls, patients with alcoholic liver disease, or patients with hepatitis C.
In a 2-stage genomewide association study involving a total of 536 patients with primary biliary cirrhosis (PBC) and 1,536 controls, Hirschfield et al. (2009) found significant and reproducible association between PBC and 2 SNPs at the IL12A locus (161560) on chromosome 3q25.33, rs6441286 (combined p = 2.42 x 10(-14); odds ratio, 1.54) and rs574808 (combined p = 1.88 x 10(-13); odds ratio, 1.54). Fine-mapping analysis showed that a 5-allele haplotype in the 3-prime flank of IL12A was significantly associated with PBC (combined p = 1.15 x 10(-34)). Hirschfield et al. (2009) also found significant association with PBC on chromosome 6p21.3 (PBC2; 613007) and chromosome 1p31.2 (PBC3; 613008). In addition, there was a modest genomewide association (combined p less than 5.0 x 10(-5)) with risk of disease for SNPs at the STAT4 (600558) and CTLA4 (123890) loci on chromosome 2q32-q33 as well as 10 other loci.
To replicate the findings of Hirschfield et al. (2009) and to evaluate the relevance of identified loci to PBC susceptibility, Hirschfield et al. (2010) tested an additional independent cohort of 857 individuals with PBC and 3,198 controls, all of European descent, for PBC associations with 36 SNPs across 24 loci. The combination of these replication results and the prior genomewide association data yielded a genetic dataset derived from 1,351 PBC cases and 4,700 controls. The locus on chromosome 7q32 (PBC4; 614220) near the IRF5 (607218)-TNPO3 (610032) genes was confirmed by this analysis (rs10488631, replication dataset p = 1.13 x 10(-8), OR = 1.58; combined dataset p = 8.66 x 10(-13), OR = 1.57). Fine mapping at this locus showed that the strongest signals were from rs12539741 and rs2070197 alleles. These variants map to just 3-prime of the IRF5 coding region and are in tight linkage disequilibrium with one another, and their associations with PBC reached fine-mapping p values of 1.65 x 10(-10) (odds ratio = 1.63) and 3.74 x 10(-10) (odds ratio = 1.62), respectively. Hirschfield et al. (2010) also identified association with PBC at a region on chromosome 17q12-q21 (PBC5; 614221) represented by rs11557467 in the ZPBP2 gene (608499) (combined p = 3.5 x 10(-13), OR = 0.72). Finally, Hirschfield et al. (2010) identified rs3890745 in the MMEL1 gene, with a combined p value of 2.28 x 10(-9) (odds ratio = 1.32), as a PBC susceptibility locus. Hirschfield et al. (2010) concluded that as these loci are implicated in other autoimmune conditions, these findings confirm genetic overlap among such diseases.
Liu et al. (2010) performed a genomewide association study for primary biliary cirrhosis risk alleles in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB (PBC1 and PBC3) associations, and a combined meta-analysis using a Canadian dataset identified associated loci at SPIB (606802) (p = 7.9 x 10(-11), odds ratio = 1.46), IRF5-TNPO3 (PBC4) (p = 2.8 x 10(-10), odds ratio = 1.63), and 17q12-q21 (PBC5) (p = 1.69 x 10(-9), odds ratio = 1.38).
The study of Liu et al. (2012) using dense genotyping across autoimmune disease-associated loci increased the number of primary biliary cirrhosis susceptibility loci to 25.
Coppel, R. L., McNeilage, L. J., Surh, C. D., Van de Water, J., Spithill, T. W., Whittingham, S., Gershwin, M. E. Primary structure of the human M2 mitochondrial autoantigen of primary biliary cirrhosis: dihydrolipoamide acetyltransferase. Proc. Nat. Acad. Sci. 85: 7317-7321, 1988. [PubMed: 3174635] [Full Text: https://doi.org/10.1073/pnas.85.19.7317]
Courvalin, J.-C., Lassoued, K., Worman, H. J., Blobel, G. Identification and characterization of autoantibodies against the nuclear envelope lamin B receptor from patients with primary biliary cirrhosis. J. Exp. Med. 172: 961-967, 1990. [PubMed: 2167346] [Full Text: https://doi.org/10.1084/jem.172.3.961]
Graham, A. M., Dollinger, M. M., Howie, S. E. M., Harrison, D. J. Identification of novel alleles at a polymorphic microsatellite repeat region in the human NRAMP1 gene promoter: analysis of allele frequencies in primary biliary cirrhosis. J. Med. Genet. 37: 150-152, 2000. [PubMed: 10712108] [Full Text: https://doi.org/10.1136/jmg.37.2.150]
Hirakata, M., Akizuki, M., Miyachi, K., Matsushima, H., Okano, T., Homma, M. Coexistence of CREST syndrome and primary biliary cirrhosis: serological studies of two cases. J. Rheum. 15: 1166-1170, 1988. [PubMed: 3172118]
Hirschfield, G. M., Liu, X., Han, Y., Gorlov, I. P., Lu, Y., Xu, C., Lu, Y., Chen, W., Juran, B. D., Coltescu, C., Mason, A. L., Milkiewicz, P., and 12 others. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nature Genet. 42: 655-657, 2010. [PubMed: 20639879] [Full Text: https://doi.org/10.1038/ng.631]
Hirschfield, G. M., Liu, X., Xu, C., Lu, Y., Xie, G., Lu, Y., Gu, X., Walker, E. J., Jing, K., Juran, B. D., Mason, A. L., Myers, R. P., Peltekian, K. M., Ghent, C. N., Coltescu, C., Atkinson, E. J., Heathcote, E. J., Lazaridis, K. N., Amos, C. I., Siminovitch, K. A. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. New Eng. J. Med. 360: 2544-2555, 2009. Note: Erratum: New Eng. J. Med. 360: 2797-2798, 2009. [PubMed: 19458352] [Full Text: https://doi.org/10.1056/NEJMoa0810440]
Jaup, B. H., Zettergren, L. S. W. Familial occurrence of primary biliary cirrhosis associated with hypergammaglobulinemia in descendants: a family study. Gastroenterology 78: 549-555, 1980. [PubMed: 6965374]
Kaplan, M. M. Primary biliary cirrhosis. New Eng. J. Med. 335: 1570-1580, 1996. [PubMed: 8900092] [Full Text: https://doi.org/10.1056/NEJM199611213352107]
Liu, J. Z., Almarri, M. A., Gaffney, D. J., Mells, G. F., Jostins, L., Cordell, H. J., Ducker, S. J., Day, D. B., Heneghan, M. A., Neuberger, J. M., Donaldson, P. T., Bathgate, A. J., and 9 others. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nature Genet. 44: 1137-1141, 2012. [PubMed: 22961000] [Full Text: https://doi.org/10.1038/ng.2395]
Liu, X., Invernizzi, P., Lu, Y., Kosoy, R., Lu, Y., Bianchi, I., Podda, M., Xu, C., Xie, G., Macciardi, F., Selmi, C., Lupoli, S., and 60 others. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nature Genet. 42: 658-660, 2010. [PubMed: 20639880] [Full Text: https://doi.org/10.1038/ng.627]
Miller, K. B., Sepersky, R. A., Brown, K. M., Goldberg, M. J., Kaplan, M. M. Genetic abnormalities of immunoregulation in primary biliary cirrhosis. Am. J. Med. 75: 75-80, 1983. [PubMed: 6222651] [Full Text: https://doi.org/10.1016/0002-9343(83)91170-1]
Szostecki, C., Guldner, H. H., Netter, H. J., Will, H. Isolation and characterization of cDNA encoding a human nuclear antigen predominantly recognized by autoantibodies from patients with primary biliary cirrhosis. J. Immun. 145: 4338-4347, 1990. [PubMed: 2258622]
Tsuji, H., Murai, K., Akagi, K., Fujishima, M. Familial primary biliary cirrhosis associated with impaired concanavalin A-induced lymphocyte transformation in relatives: two family studies. Digest. Dis. Sci. 37: 353-360, 1992. [PubMed: 1735358] [Full Text: https://doi.org/10.1007/BF01307727]
Ye, Q., Worman, H. J. Primary structure analysis and lamin B and DNA binding of human LBR, an integral protein of the nuclear envelope inner membrane. J. Biol. Chem. 269: 11306-11311, 1994. [PubMed: 8157662]