Progress in the Genetics of Primary Biliary Cirrhosis

ABSTRACT

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that has a prevalence of 1 in 1000 women over the age of 40. Treatment is presently limited to ursodeoxycholic acid, a hydrophilic bile acid that has nonspecific, choleretic, effects in cholestatic liver disease. PBC has strong autoimmune features, including highly specific loss of tolerance to a ubiquitous mitochondrial antigen. Both environmental and genetic factors are considered important in the pathogenesis of disease. Prior to the advent of genome-wide association studies, only class II human leucocyte antigen (HLA) loci (HLA-DRB1*08, *11, and *13) had been reproducibly shown to associate with disease. Non-HLA loci were suggested for several genes (e.g., CTLA-4, MDR3), but often inconclusively replicated. With the application of genome-wide technology, HLA was confirmed as the strongest association and many other risk loci have been identified, with equivalent effect size to HLA, including IL12A, IL12RB2, STAT4, IRF5-TNPO3, 17q12.21, MMEL1, SPIB, and CTLA-4. These collectively support an important role for innate and adaptive immunity in development of disease. Further insights are predicted as studies with larger cohorts are assembled, and different approaches are taken to further discover common and uncommon gene variants associated with disease. Disease subphenotypes such as response to therapy, clinical progression, and symptoms remain additional areas for further dedicated studies, and in which different genetic risk factors may be relevant. Identification of risk loci associated with disease has the potential to aid development of rational, disease-specific, therapies in the future.

KEYWORDS

Primary biliary cirrhosis - genome-wide association study - IL12 - IRF5 - Innate immunity - adaptive immunity

REFERENCES

• 1 Lindor K D, Gershwin M E, Poupon R, Kaplan M, Bergasa N V, Heathcote E J. American Association for Study of Liver Diseases . Primary biliary cirrhosis.  Hepatology. 2009;  50 (1) 291-308
• 2 Hirschfield G M, Heathcote E J, Gershwin M E. Pathogenesis of cholestatic liver disease and therapeutic approaches.  Gastroenterology. 2010;  139 (5) 1481-1496
• 3 Gershwin M E, Mackay I R. The causes of primary biliary cirrhosis: Convenient and inconvenient truths.  Hepatology. 2008;  47 (2) 737-745
• 4 Walker J G, Bates D, Doniach D, Ball P A, Sherlock S. Chronic liver disease and mitochondrial antibodies: a family study.  BMJ. 1972;  1 (5793) 146-148
• 5 Chohan M R. Primary biliary cirrhosis in twin sisters.  Gut. 1973;  14 (3) 213-214
• 6 Williams M, Smith P M, Doniach D. Primary biliary cirrhosis and chronic active hepatitis in two sisters.  BMJ. 1976;  2 (6035) 566
• 7 Gershwin M E, Selmi C, Worman H J USA PBC Epidemiology Group et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients.  Hepatology. 2005;  42 (5) 1194-1202
• 8 Lazaridis K N, Juran B D, Boe G M et al.. Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis.  Hepatology. 2007;  46 (3) 785-792
• 9 Jones D E, Watt F E, Metcalf J V, Bassendine M F, James O F. Familial primary biliary cirrhosis reassessed: a geographically-based population study.  J Hepatol. 1999;  30 (3) 402-407
• 10 Selmi C, Mayo M J, Bach N et al.. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment.  Gastroenterology. 2004;  127 (2) 485-492
• 11 Arbour L, Rupps R, Field L et al.. Characteristics of primary biliary cirrhosis in British Columbia's First Nations population.  Can J Gastroenterol. 2005;  19 (5) 305-310
• 12 Watt F E, James O F, Jones D E. Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study.  QJM. 2004;  97 (7) 397-406
• 13 Invernizzi P, Gershwin M E. The genetics of human autoimmune disease.  J Autoimmun. 2009;  33 (3-4) 290-299
• 14 Ueno Y, Ambrosini Y M, Moritoki Y, Ridgway W M, Gershwin M E. Murine models of autoimmune cholangitis.  Curr Opin Gastroenterol. 2010;  26 (3) 274-279
• 15 Hirschfield G M, Liu X, Xu C et al.. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.  N Engl J Med. 2009;  360 (24) 2544-2555
• 16 Karlsen T H, Franke A, Melum E et al.. Genome-wide association analysis in primary sclerosing cholangitis.  Gastroenterology. 2010;  138 (3) 1102-1111
• 17 Donaldson P T, Doherty D G, Hayllar K M, McFarlane I G, Johnson P J, Williams R. Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors.  Hepatology. 1991;  13 (4) 701-706
• 18 Daly A K, Donaldson P T, Bhatnagar P DILIGEN Study et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin.  Nat Genet. 2009;  41 (7) 816-819
• 19 Donaldson P T, Baragiotta A, Heneghan M A et al.. HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: a large-scale study.  Hepatology. 2006;  44 (3) 667-674
• 20 Invernizzi P, Selmi C, Poli F et al.. HLA DRB1 polymorphisms in 676 Italian patients with primary biliary cirrhosis and 2028 matched healthy controls. A nation-wide population based case-control study.  Hepatology. 2005;  42 462A
• 21 Onishi S, Sakamaki T, Maeda T et al.. DNA typing of HLA class II genes; DRB1*0803 increases the susceptibility of Japanese to primary biliary cirrhosis.  J Hepatol. 1994;  21 (6) 1053-1060
• 22 Invernizzi P, Selmi C, Poli F Italian PBC Genetic Study Group et al. Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: a multicenter study of 664 patients and 1992 healthy controls.  Hepatology. 2008;  48 (6) 1906-1912
• 23 Hirschfield G M, Liu X, Han Y et al.. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis.  Nat Genet. 2010;  42 (8) 655-657
• 24 Nakamura M, Yasunami M, Kondo H PBC Study Group in NHOSLJ* et al. 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.  Hepatol Res. 2010;  40 (5) 494-504
• 25 Poupon R, Ping C, Chrétien Y et al.. Genetic factors of susceptibility and of severity in primary biliary cirrhosis.  J Hepatol. 2008;  49 (6) 1038-1045
• 26 Juran B D, Atkinson E J, Schlicht E M, Fridley B L, Lazaridis K N. Primary biliary cirrhosis is associated with a genetic variant in the 3′ flanking region of the CTLA4 gene.  Gastroenterology. 2008;  135 (4) 1200-1206
• 27 Walker E J, Hirschfield G M, Xu C et al.. CTLA4/ICOS gene variants and haplotypes are associated with rheumatoid arthritis and primary biliary cirrhosis in the Canadian population.  Arthritis Rheum. 2009;  60 (4) 931-937
• 28 Juran B D, Atkinson E J, Larson J J et al.. 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. 2010;  52 (1) 223-229
• 29 Juran B D, Atkinson E J, Schlicht E M, Fridley B L, Petersen G M, Lazaridis K N. Interacting alleles of the coinhibitory immunoreceptor genes cytotoxic T-lymphocyte antigen 4 and programmed cell-death 1 influence risk and features of primary biliary cirrhosis.  Hepatology. 2008;  47 (2) 563-570
• 30 Karlsen T H, Melum E, Franke A. The utility of genome-wide association studies in hepatology.  Hepatology. 2010;  51 (5) 1833-1842
• 31 Liu X, Invernizzi P, Lu Y et al.. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis.  Nat Genet. 2010;  42 (8) 658-660
• 32 Hirschfield G M, Siminovitch K A. Toward the molecular dissection of primary biliary cirrhosis.  Hepatology. 2009;  50 (5) 1347-1350
• 33 Invernizzi P, Miozzo M, Battezzati P M et al.. Frequency of monosomy X in women with primary biliary cirrhosis.  Lancet. 2004;  363 (9408) 533-535
• 34 Miozzo M, Selmi C, Gentilin B et al.. Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis.  Hepatology. 2007;  46 (2) 456-462
• 35 Mitchell M M, Lleo A, Zammataro L et al.. Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis.  Epigenetics. 2011;  6 (1)
• 36 Surolia I, Pirnie S P, Chellappa V et al.. Functionally defective germline variants of sialic acid acetylesterase in autoimmunity.  Nature. 2010;  466 (7303) 243-247
• 37 Zhong B, Strnad P, Selmi C et al.. Keratin variants are overrepresented in primary biliary cirrhosis and associate with disease severity.  Hepatology. 2009;  50 (2) 546-554
• 38 Hamlyn A N, Macklon A F, James O. Primary biliary cirrhosis: geographical clustering and symptomatic onset seasonality.  Gut. 1983;  24 (10) 940-945
• 39 Myszor M, James O F. The epidemiology of primary biliary cirrhosis in north-east England: an increasingly common disease?.  Q J Med. 1990;  75 (276) 377-385
• 40 Danielsson A, Boqvist L, Uddenfeldt P. Epidemiology of primary biliary cirrhosis in a defined rural population in the northern part of Sweden.  Hepatology. 1990;  11 (3) 458-464
• 41 Bach N, Schaffner F. Familial primary biliary cirrhosis.  J Hepatol. 1994;  20 (6) 698-701
• 42 Brind A M, Bray G P, Portmann B C, Williams R. Prevalence and pattern of familial disease in primary biliary cirrhosis.  Gut. 1995;  36 (4) 615-617
• 43 Floreani A, Naccarato R, Chiaramonte M. Prevalence of familial disease in primary biliary cirrhosis in Italy.  J Hepatol. 1997;  26 (3) 737-738
• 44 Tsuji K, Watanabe Y, Van De Water J et al.. Familial primary biliary cirrhosis in Hiroshima.  J Autoimmun. 1999;  13 (1) 171-178
• 45 Bittencourt P L, Farias A Q, Abrantes-Lemos C P et al.. Prevalence of immune disturbances and chronic liver disease in family members of patients with primary biliary cirrhosis.  J Gastroenterol Hepatol. 2004;  19 (8) 873-878
• 46 Olafsson S, Gudjonsson H, Selmi C et al.. Antimitochondrial antibodies and reactivity to N. aromaticivorans proteins in Icelandic patients with primary biliary cirrhosis and their relatives.  Am J Gastroenterol. 2004;  99 (11) 2143-2146
• 47 Hayase Y, Iwasaki S, Akisawa N et al.. Similar anti-mitochondrial antibody reactivity profiles in familial primary biliary cirrhosis.  Hepatol Res. 2005;  33 (1) 33-38
• 48 Yanagisawa M, Takagi H, Takahashi H et al.. Familial clustering and genetic background of primary biliary cirrhosis in Japan.  Dig Dis Sci. 2010;  55 (9) 2651-2658
• 49 Invernizzi P, Battezzati P M, Crosignani A et al.. Peculiar HLA polymorphisms in Italian patients with primary biliary cirrhosis.  J Hepatol. 2003;  38 (4) 401-406
• 50 Zappala F, Grove J, Watt F E et al.. No evidence for involvement of the interleukin-10 -592 promoter polymorphism in genetic susceptibility to primary biliary cirrhosis.  J Hepatol. 1998;  28 (5) 820-823
• 51 Matsushita M, Tanaka A, Kikuchi K et al.. Association of single nucleotide polymorphisms of the interleukin-10 promoter gene and susceptibility to primary biliary cirrhosis: immunogenetic differences in Italian and Japanese patients.  Autoimmunity. 2002;  35 (8) 531-536
• 52 Fan L Y, Tu X Q, Zhu Y et al.. Genetic association of cytokines polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese.  World J Gastroenterol. 2005;  11 (18) 2768-2772
• 53 Gordon M A, Oppenheim E, Camp N J, di Giovine F S, Duff G W, Gleeson D. Primary biliary cirrhosis shows association with genetic polymorphism of tumour necrosis factor alpha promoter region.  J Hepatol. 1999;  31 (2) 242-247
• 54 Tanaka A, Quaranta S, Mattalia A et al.. The tumor necrosis factor-alpha promoter correlates with progression of primary biliary cirrhosis.  J Hepatol. 1999;  30 (5) 826-829
• 55 Niro G A, Poli F, Andriulli A et al.. TNF-alpha polymorphisms in primary biliary cirrhosis: a northern and southern Italian experience.  Ann N Y Acad Sci. 2009;  1173 557-563
• 56 Graham A M, Dollinger M M, Howie S E, 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. 2000;  37 (2) 150-152
• 57 Agarwal K, Czaja A J, Jones D E, Donaldson P T. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis.  Hepatology. 2000;  31 (1) 49-53
• 58 Bittencourt P L, Palácios S A, Farias A Q et al.. Analysis of major histocompatibility complex and CTLA-4 alleles in Brazilian patients with primary biliary cirrhosis.  J Gastroenterol Hepatol. 2003;  18 (9) 1061-1066
• 59 Joshita S, Umemura T, Yoshizawa K Shinshu PBC Study Group et al. Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients.  J Hepatol. 2010;  53 (3) 537-541
• 60 Donaldson P, Agarwal K, Craggs A, Craig W, James O, Jones D. HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility.  Gut. 2001;  48 (3) 397-402
• 61 Lakatos L P, Bajnok E, Hegedus D, Tóth T, Lakatos P, Szalay F. Vitamin D receptor, oestrogen receptor-alpha gene and interleukin-1 receptor antagonist gene polymorphisms in Hungarian patients with primary biliary cirrhosis.  Eur J Gastroenterol Hepatol. 2002;  14 (7) 733-740
• 62 Vogel A, Strassburg C P, Manns M P. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis.  Hepatology. 2002;  35 (1) 126-131
• 63 Halmos B, Szalay F, Cserniczky T et al.. Association of primary biliary cirrhosis with vitamin D receptor BsmI genotype polymorphism in a Hungarian population.  Dig Dis Sci. 2000;  45 (6) 1091-1095
• 64 Tanaka A, Nezu S, Uegaki S et al.. Vitamin D receptor polymorphisms are associated with increased susceptibility to primary biliary cirrhosis in Japanese and Italian populations.  J Hepatol. 2009;  50 (6) 1202-1209
• 65 Joshita S, Umemura T, Yoshizawa K, Katsuyama Y, Tanaka E, Ota M. Shinshu PBC Study Group . A2BP1 as a novel susceptible gene for primary biliary cirrhosis in Japanese patients.  Hum Immunol. 2010;  71 (5) 520-524
• 66 Mells G F, Floyd J A, Morley K I et al.. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis.  Nat Genet. 2011;  43 (4) 329-32