Semin Liver Dis 2015; 35(04): 392-401
DOI: 10.1055/s-0035-1567831
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Genome-Wide Association Studies in Primary Biliary Cirrhosis

Aliya F. Gulamhusein
1   Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
,
Brian D. Juran
1   Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
,
Konstantinos N. Lazaridis
1   Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
› Author Affiliations
Further Information

Publication History

Publication Date:
16 December 2015 (online)

Abstract

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.

 
  • References

  • 1 Kim WR, Lindor KD, Locke III GR , et al. Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology 2000; 119 (6) 1631-1636
  • 2 Hirschfield GM, Gershwin ME. The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol 2013; 8: 303-330
  • 3 Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ ; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology 2009; 50 (1) 291-308
  • 4 Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol 2011; 55 (6) 1361-1367
  • 5 Bach N, Schaffner F. Familial primary biliary cirrhosis. J Hepatol 1994; 20 (6) 698-701
  • 6 Selmi C, Mayo MJ, Bach N , et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 2004; 127 (2) 485-492
  • 7 Jones DE, Watt FE, Metcalf JV, Bassendine MF, James OF. Familial primary biliary cirrhosis reassessed: a geographically-based population study. J Hepatol 1999; 30 (3) 402-407
  • 8 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 (3) 785-792
  • 9 Abecasis GR, Auton A, Brooks LD , et al; 1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 2012; 491 (7422) 56-65
  • 10 Juran BD, Lazaridis KN. Genomics in the post-GWAS era. Semin Liver Dis 2011; 31 (2) 215-222
  • 11 Leung PS, Van de Water J, Coppel RL, Gershwin ME. Molecular characterization of the mitochondrial autoantigens in primary biliary cirrhosis. Immunol Res 1991; 10 (3–4) 518-527
  • 12 Kita H, Matsumura S, He XS , et al. Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J Clin Invest 2002; 109 (9) 1231-1240
  • 13 Shimoda S, Nakamura M, Ishibashi H, Hayashida K, Niho Y. HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. J Exp Med 1995; 181 (5) 1835-1845
  • 14 Harada K, Van de Water J, Leung PS , et al. In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis: predominance of the Th1 subset. Hepatology 1997; 25 (4) 791-796
  • 15 Yeaman SJ, Fussey SP, Danner DJ, James OF, Mutimer DJ, Bassendine MF. Primary biliary cirrhosis: identification of two major M2 mitochondrial autoantigens. Lancet 1988; 1 (8594) 1067-1070
  • 16 Fussey SP, Guest JR, James OF, Bassendine MF, Yeaman SJ. Identification and analysis of the major M2 autoantigens in primary biliary cirrhosis. Proc Natl Acad Sci U S A 1988; 85 (22) 8654-8658
  • 17 Lleo A, Selmi C, Invernizzi P , et al. Apotopes and the biliary specificity of primary biliary cirrhosis. Hepatology 2009; 49 (3) 871-879
  • 18 Lleo A, Bowlus CL, Yang GX , et al. Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis. Hepatology 2010; 52 (3) 987-998
  • 19 Wang L, Wang FS, Chang C, Gershwin ME. Breach of tolerance: primary biliary cirrhosis. Semin Liver Dis 2014; 34 (3) 297-317
  • 20 Invernizzi P. Human leukocyte antigen in primary biliary cirrhosis: an old story now reviving. Hepatology 2011; 54 (2) 714-723
  • 21 Begovich AB, Klitz W, Moonsamy PV, Van de Water J, Peltz G, Gershwin ME. Genes within the HLA class II region confer both predisposition and resistance to primary biliary cirrhosis. Tissue Antigens 1994; 43 (2) 71-77
  • 22 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 (3) 667-674
  • 23 Mullarkey ME, Stevens AM, McDonnell WM , et al. Human leukocyte antigen class II alleles in Caucasian women with primary biliary cirrhosis. Tissue Antigens 2005; 65 (2) 199-205
  • 24 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
  • 25 Invernizzi P, Selmi C, Poli F , et al; Italian PBC Genetic Study Group. 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
  • 26 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
  • 27 Gordon MA, Oppenheim E, Camp NJ, di Giovine FS, Duff GW, Gleeson D. Primary biliary cirrhosis shows association with genetic polymorphism of tumour necrosis factor alpha promoter region. J Hepatol 1999; 31 (2) 242-247
  • 28 Graham AM, Dollinger MM, Howie SE, Harrison DJ. 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
  • 29 Walker EJ, Hirschfield GM, 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
  • 30 Juran BD, Atkinson EJ, Larson JJ , 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
  • 31 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
  • 32 Vogel A, Strassburg CP, Manns MP. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis. Hepatology 2002; 35 (1) 126-131
  • 33 Juran BD, Atkinson EJ, Schlicht EM, Fridley BL, Petersen GM, Lazaridis KN. 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
  • 34 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 (4) 1200-1206
  • 35 Hirschfield GM, Invernizzi P. Progress in the genetics of primary biliary cirrhosis. Semin Liver Dis 2011; 31 (2) 147-156
  • 36 Hirschfield GM, 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
  • 37 Nakamura M, Yasunami M, Kondo H , et al; PBC Study Group in NHOSLJ*. 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
  • 38 Fernando MM, Stevens CR, Walsh EC , et al. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet 2008; 4 (4) e1000024
  • 39 Hirschfield GM, 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
  • 40 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
  • 41 Mells GF, Floyd JA, Morley KI , et al; UK PBC Consortium; Wellcome Trust Case Control Consortium 3. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet 2011; 43 (11) 1164
  • 42 Nakamura M, Nishida N, Kawashima M , et al. Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. Am J Hum Genet 2012; 91 (4) 721-728
  • 43 Cortes A, Brown MA. Promise and pitfalls of the Immunochip. Arthritis Res Ther 2011; 13 (1) 101
  • 44 Liu JZ, Almarri MA, Gaffney DJ , et al; UK Primary Biliary Cirrhosis (PBC) Consortium; Wellcome Trust Case Control Consortium 3. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat Genet 2012; 44 (10) 1137-1141
  • 45 Juran BD, Hirschfield GM, Invernizzi P , et al; Italian PBC Genetics Study Group. Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. Hum Mol Genet 2012; 21 (23) 5209-5221
  • 46 Kar SP, Seldin MF, Chen W , et al; Italian PBC Genetics Study Group. Pathway-based analysis of primary biliary cirrhosis genome-wide association studies. Genes Immun 2013; 14 (3) 179-186
  • 47 Carbone M, Lleo A, Sandford RN, Invernizzi P. Implications of genome-wide association studies in novel therapeutics in primary biliary cirrhosis. Eur J Immunol 2014; 44 (4) 945-954
  • 48 van Wanrooij RL, Zwiers A, Kraal G, Bouma G. Genetic variations in interleukin-12 related genes in immune-mediated diseases. J Autoimmun 2012; 39 (4) 359-368
  • 49 Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 2003; 3 (2) 133-146
  • 50 Lleo A, Gershwin ME, Mantovani A, Invernizzi P. Towards common denominators in primary biliary cirrhosis: the role of IL-12. J Hepatol 2012; 56 (3) 731-733
  • 51 Vignali DA, Kuchroo VK. IL-12 family cytokines: immunological playmakers. Nat Immunol 2012; 13 (8) 722-728
  • 52 Hirschfield GM, Chapman RW, Karlsen TH, Lammert F, Lazaridis KN, Mason AL. The genetics of complex cholestatic disorders. Gastroenterology 2013; 144 (7) 1357-1374
  • 53 Krausgruber T, Blazek K, Smallie T , et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol 2011; 12 (3) 231-238
  • 54 Gershwin ME, Selmi C, Worman HJ , et al; USA PBC Epidemiology Group. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 2005; 42 (5) 1194-1202
  • 55 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 (4) 395-402
  • 56 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 (10) 977-986
  • 57 Li Y, Zhang K, Chen H , et al. A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren's syndrome at 7q11.23. Nat Genet 2013; 45 (11) 1361-1365
  • 58 Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol 2002; 2 (10) 725-734
  • 59 Elsharkawy AM, Oakley F, Lin F, Packham G, Mann DA, Mann J. The NF-kappaB p50:p50:HDAC-1 repressor complex orchestrates transcriptional inhibition of multiple pro-inflammatory genes. J Hepatol 2010; 53 (3) 519-527
  • 60 Oakley F, Mann J, Nailard S , et al. Nuclear factor-kappaB1 (p50) limits the inflammatory and fibrogenic responses to chronic injury. Am J Pathol 2005; 166 (3) 695-708
  • 61 Barrett JC, Clayton DG, Concannon P , et al; Type 1 Diabetes Genetics Consortium. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 2009; 41 (6) 703-707
  • 62 Franke A, McGovern DP, Barrett JC , et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 2010; 42 (12) 1118-1125
  • 63 Anderson CA, Boucher G, Lees CW , et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 2011; 43 (3) 246-252
  • 64 Bianchi I, Carbone M, Lleo A, Invernizzi P. Genetics and epigenetics of primary biliary cirrhosis. Semin Liver Dis 2014; 34 (3) 255-264
  • 65 Kawata K, Tsuda M, Yang GX , et al. Identification of potential cytokine pathways for therapeutic intervention in murine primary biliary cirrhosis. PLoS ONE 2013; 8 (9) e74225
  • 66 Kawata K, Yang GX, Ando Y , et al. Clonality, activated antigen-specific CD8(+) T cells, and development of autoimmune cholangitis in dnTGFβRII mice. Hepatology 2013; 58 (3) 1094-1104
  • 67 Ando Y, Yang GX, Kenny TP , et al. Overexpression of microRNA-21 is associated with elevated pro-inflammatory cytokines in dominant-negative TGF-β receptor type II mouse. J Autoimmun 2013; 41: 111-119
  • 68 Dhirapong A, Yang GX, Nadler S , et al. Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis. Hepatology 2013; 57 (2) 708-715
  • 69 Ebert EC, Panja A, Das KM , et al. Patients with inflammatory bowel disease may have a transforming growth factor-beta-, interleukin (IL)-2- or IL-10-deficient state induced by intrinsic neutralizing antibodies. Clin Exp Immunol 2009; 155 (1) 65-71
  • 70 Kel JM, Girard-Madoux MJ, Reizis B, Clausen BE. TGF-beta is required to maintain the pool of immature Langerhans cells in the epidermis. J Immunol 2010; 185 (6) 3248-3255
  • 71 Yoshida K, Yang GX, Zhang W , et al. Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor beta receptor type II mice. Hepatology 2009; 50 (5) 1494-1500
  • 72 Tsuda M, Zhang W, Yang GX , et al. Deletion of interleukin (IL)-12p35 induces liver fibrosis in dominant-negative TGFβ receptor type II mice. Hepatology 2013; 57 (2) 806-816
  • 73 Wakabayashi K, Lian ZX, Leung PS , et al. Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. Hepatology 2008; 48 (2) 531-540
  • 74 Wakabayashi K, Yoshida K, Leung PS , et al. Induction of autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization. Clin Exp Immunol 2009; 155 (3) 577-586
  • 75 Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet 2010; 11 (6) 415-425
  • 76 Pritchard JK. Are rare variants responsible for susceptibility to complex diseases?. Am J Hum Genet 2001; 69 (1) 124-137
  • 77 Tang R, Chen H, Miao Q , et al. The cumulative effects of known susceptibility variants to predict primary biliary cirrhosis risk. Genes Immun 2015; 16 (3) 193-198
  • 78 Mannon PJ, Fuss IJ, Mayer L , et al; Anti-IL-12 Crohn's Disease Study Group. Anti-interleukin-12 antibody for active Crohn's disease. N Engl J Med 2005; 352 (12) 1276
  • 79 Tan JY, Li S, Yang K , et al. Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: a meta-analysis. J Dermatolog Treat 2011; 22 (6) 323-336
  • 80 Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 2005; 23: 515-548
  • 81 Scalapino KJ, Daikh DI. CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev 2008; 223: 143-155
  • 82 Najafian N, Sayegh MH. CTLA4-Ig: a novel immunosuppressive agent. Expert Opin Investig Drugs 2000; 9 (9) 2147-2157
  • 83 Genovese MC, Becker JC, Schiff M , et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005; 353 (11) 1114-1123
  • 84 Abrams JR, Lebwohl MG, Guzzo CA , et al. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest 1999; 103 (9) 1243-1252
  • 85 Tacke F, Luedde T, Trautwein C. Inflammatory pathways in liver homeostasis and liver injury. Clin Rev Allergy Immunol 2009; 36 (1) 4-12
  • 86 Strubin M, Newell JW, Matthias P. OBF-1, a novel B cell-specific coactivator that stimulates immunoglobulin promoter activity through association with octamer-binding proteins. Cell 1995; 80 (3) 497-506
  • 87 Cortés M, Georgopoulos K. Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity. J Exp Med 2004; 199 (2) 209-219
  • 88 Garrett-Sinha LA, Su GH, Rao S , et al. PU.1 and Spi-B are required for normal B cell receptor-mediated signal transduction. Immunity 1999; 10 (4) 399-408
  • 89 Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol 2011; 11 (5) 330-342
  • 90 Myers RP, Swain MG, Lee SS, Shaheen AA, Burak KW. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J Gastroenterol 2013; 108 (6) 933-941
  • 91 Dhirapong A, Lleo A, Yang GX , et al. B cell depletion therapy exacerbates murine primary biliary cirrhosis. Hepatology 2011; 53 (2) 527-535