Genetics and Epigenetics of Primary Biliary Cirrhosis

 

 Buy Article Permissions and Reprints

Abstract

Primary biliary cirrhosis (PBC) has been considered a multifactorial autoimmune disease presumably arising from a combination of environmental and genetic factors, with genetic inheritance mostly suggested by familial occurrence and high concordance rate among monozygotic twins. In the last decade, genome-wide association studies, new data on sex chromosome defects and instabilities, and initial evidence on the role of epigenetic abnormalities have strengthened the crucial importance of genetic and epigenetic factors in determining the susceptibility of PBC. High-throughput genetic studies in particular have revolutionized the search for genetic influences on PBC and have the potential to be translated into clinical and therapeutic applications, although more biological knowledge on candidate genes is now needed. In this review, these recent discoveries will be critically summarized with particular focus on the possible steps that may transfer genetic and epigenetic knowledge to direct health benefits in patients with PBC.

• References

• 1 Invernizzi P, Selmi C, Gershwin ME. Update on primary biliary cirrhosis. Dig Liver Dis 2010; 42 (6) 401-408
  CrossrefPubMedGoogle Scholar
• 2 Lleo A, Invernizzi P. Apotopes and innate immune system: novel players in the primary biliary cirrhosis scenario. Dig Liver Dis 2013; 45 (8) 630-636
  CrossrefPubMedGoogle Scholar
• 3 Podda M, Selmi C, Lleo A, Moroni L, Invernizzi P. The limitations and hidden gems of the epidemiology of primary biliary cirrhosis. J Autoimmun 2013; 46: 81-87
  CrossrefPubMedGoogle Scholar
• 4 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
  CrossrefPubMedGoogle Scholar
• 5 Ando Y, Yang GX, Tsuda M , et al. The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17A deleted dominant negative form of transforming growth factor beta receptor type II mice. Hepatology 2012; 56 (4) 1418-1426
  CrossrefPubMedGoogle Scholar
• 6 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009; 51 (2) 237-267
  CrossrefPubMedGoogle Scholar
• 7 Invernizzi P, Battezzati PM, Crosignani A , et al. Peculiar HLA polymorphisms in Italian patients with primary biliary cirrhosis. J Hepatol 2003; 38 (4) 401-406
  CrossrefPubMedGoogle Scholar
• 8 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
  CrossrefPubMedGoogle Scholar
• 9 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
  CrossrefPubMedGoogle Scholar
• 10 Invernizzi P. Human leukocyte antigen in primary biliary cirrhosis: an old story now reviving. Hepatology 2011; 54 (2) 714-723
  CrossrefPubMedGoogle Scholar
• 11 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
  CrossrefPubMedGoogle Scholar
• 12 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
  CrossrefPubMedGoogle Scholar
• 13 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
  PubMedGoogle Scholar
• 14 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
  CrossrefPubMedGoogle Scholar
• 15 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
  CrossrefPubMedGoogle Scholar
• 16 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
  CrossrefPubMedGoogle Scholar
• 17 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
  CrossrefPubMedGoogle Scholar
• 18 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
  CrossrefPubMedGoogle Scholar
• 19 Bach N, Schaffner F. Familial primary biliary cirrhosis. J Hepatol 1994; 20 (6) 698-701
  CrossrefPubMedGoogle Scholar
• 20 Brind AM, Bray GP, Portmann BC, Williams R. Prevalence and pattern of familial disease in primary biliary cirrhosis. Gut 1995; 36 (4) 615-617
  CrossrefPubMedGoogle Scholar
• 21 Fagan E, Williams R, Cox S. Primary biliary cirrhosis in mother and daughter. BMJ 1977; 2 (6096) 1195
  CrossrefPubMedGoogle Scholar
• 22 Floreani A, Naccarato R, Chiaramonte M. Prevalence of familial disease in primary biliary cirrhosis in Italy. J Hepatol 1997; 26 (3) 737-738
  CrossrefPubMedGoogle Scholar
• 23 Jaup BH, Zettergren LS. Familial occurrence of primary biliary cirrhosis associated with hypergammaglobulinemia in descendants: a family study. Gastroenterology 1980; 78 (3) 549-555
  PubMedGoogle Scholar
• 24 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
  CrossrefPubMedGoogle Scholar
• 25 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
  CrossrefPubMedGoogle Scholar
• 26 Tsuji K, Watanabe Y, Van De Water J , et al. Familial primary biliary cirrhosis in Hiroshima. J Autoimmun 1999; 13 (1) 171-178
  CrossrefPubMedGoogle Scholar
• 27 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 (5) 401-410
  CrossrefPubMedGoogle Scholar
• 28 Invernizzi P. Role of X chromosome defects in primary biliary cirrhosis. Hepatol Res 2007; 37 (3) (Suppl. 03) S384-S388
  CrossrefPubMedGoogle Scholar
• 29 Milkiewicz P, Heathcote J. Primary biliary cirrhosis in a patient with Turner syndrome. Can J Gastroenterol 2005; 19 (10) 631-633
  PubMedGoogle Scholar
• 30 Invernizzi P, Pasini S, Selmi C, Gershwin ME, Podda M. Female predominance and X chromosome defects in autoimmune diseases. J Autoimmun 2009; 33 (1) 12-16
  CrossrefPubMedGoogle Scholar
• 31 Invernizzi P, Miozzo M, Battezzati PM , et al. Frequency of monosomy X in women with primary biliary cirrhosis. Lancet 2004; 363 (9408) 533-535
  CrossrefPubMedGoogle Scholar
• 32 Invernizzi P, Miozzo M, Selmi C , et al. X chromosome monosomy: a common mechanism for autoimmune diseases. J Immunol 2005; 175 (1) 575-578
  CrossrefPubMedGoogle Scholar
• 33 Invernizzi P, Miozzo M, Oertelt-Prigione S , et al. X monosomy in female systemic lupus erythematosus. Ann N Y Acad Sci 2007; 1110: 84-91
  CrossrefPubMedGoogle Scholar
• 34 Bianchi I, Lleo A, Gershwin ME, Invernizzi P. The X chromosome and immune associated genes. J Autoimmun 2012; 38 (2-3) J187-J192
  CrossrefPubMedGoogle Scholar
• 35 Lleo A, Oertelt-Prigione S, Bianchi I , et al. Y chromosome loss in male patients with primary biliary cirrhosis. J Autoimmun 2013; 41: 87-91
  CrossrefPubMedGoogle Scholar
• 36 Mitchell MM, 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) 95-102
  CrossrefPubMedGoogle Scholar
• 37 Lleo A, Liao J, Invernizzi P , et al. Immunoglobulin M levels inversely correlate with CD40 ligand promoter methylation in patients with primary biliary cirrhosis. Hepatology 2012; 55 (1) 153-160
  CrossrefPubMedGoogle Scholar
• 38 Hewagama A, Richardson B. The genetics and epigenetics of autoimmune diseases. J Autoimmun 2009; 33 (1) 3-11
  CrossrefPubMedGoogle Scholar
• 39 Duerr RH, Taylor KD, Brant SR , et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314 (5804) 1461-1463
  CrossrefPubMedGoogle Scholar
• 40 Sladek R, Rocheleau G, Rung J , et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007; 445 (7130) 881-885
  CrossrefPubMedGoogle Scholar
• 41 Collins FS, Guyer MS, Charkravarti A. Variations on a theme: cataloging human DNA sequence variation. Science 1997; 278 (5343) 1580-1581
  CrossrefPubMedGoogle Scholar
• 42 Hindorff LA, Sethupathy P, Junkins HA , et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 2009; 106 (23) 9362-9367
  CrossrefPubMedGoogle Scholar
• 43 McKay FC, Hoe E, Parnell G , et al. IL7Rα expression and upregulation by IFNβ in dendritic cell subsets is haplotype-dependent. PLoS ONE 2013; 8 (10) e77508
  CrossrefPubMedGoogle Scholar
• 44 Ouyang W, Oh SA, Ma Q, Bivona MR, Zhu J, Li MO. TGF-β cytokine signaling promotes CD8+ T cell development and low-affinity CD4+ T cell homeostasis by regulation of interleukin-7 receptor α expression. Immunity 2013; 39 (2) 335-346
  CrossrefPubMedGoogle Scholar
• 45 Tsuda M, Moritoki Y, Lian ZX , et al. Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Hepatology 2012; 55 (2) 512-521
  CrossrefPubMedGoogle Scholar
• 46 Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol 2002; 2 (10) 725-734
  CrossrefPubMedGoogle Scholar
• 47 Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 2005; 23: 515-548
  CrossrefPubMedGoogle Scholar
• 48 Scalapino KJ, Daikh DI. CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev 2008; 223: 143-155
  CrossrefPubMedGoogle Scholar
• 49 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
  CrossrefPubMedGoogle Scholar
• 50 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
  CrossrefPubMedGoogle Scholar
• 51 Kremer JM, Dougados M, Emery P , et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005; 52 (8) 2263-2271
  CrossrefPubMedGoogle Scholar
• 52 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
  CrossrefPubMedGoogle Scholar
• 53 Zhernakova A, van Diemen CC, Wijmenga C. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet 2009; 10 (1) 43-55
  CrossrefPubMedGoogle Scholar
• 54 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
  CrossrefPubMedGoogle Scholar
• 55 Becher B, Durell BG, Noelle RJ. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 2002; 110 (4) 493-497
  CrossrefPubMedGoogle Scholar
• 56 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
  CrossrefPubMedGoogle Scholar
• 57 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
  CrossrefPubMedGoogle Scholar
• 58 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
  PubMedGoogle Scholar
• 59 Burakoff R, Barish CF, Riff D , et al. A phase 1/2A trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohn's disease. Inflamm Bowel Dis 2006; 12 (7) 558-565
  CrossrefPubMedGoogle Scholar
• 60 Leonardi CL, Kimball AB, Papp KA , et al; PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371 (9625) 1665-1674
  CrossrefPubMedGoogle Scholar
• 61 Hochdörfer T, Kuhny M, Zorn CN , et al. Activation of the PI3K pathway increases TLR-induced TNF-α and IL-6 but reduces IL-1β production in mast cells. Cell Signal 2011; 23 (5) 866-875
  CrossrefPubMedGoogle Scholar
• 62 Frey RS, Gao X, Javaid K, Siddiqui SS, Rahman A, Malik AB. Phosphatidylinositol 3-kinase gamma signaling through protein kinase Czeta induces NADPH oxidase-mediated oxidant generation and NF-kappaB activation in endothelial cells. J Biol Chem 2006; 281 (23) 16128-16138
  CrossrefPubMedGoogle Scholar
• 63 Koyasu S. The role of PI3K in immune cells. Nat Immunol 2003; 4 (4) 313-319
  CrossrefPubMedGoogle Scholar
• 64 Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev 2008; 22 (18) 2454-2472
  CrossrefPubMedGoogle Scholar
• 65 Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001; 15 (23) 3059-3087
  CrossrefPubMedGoogle Scholar
• 66 Bhardwaj G, Murdoch B, Wu D , et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol 2001; 2 (2) 172-180
  CrossrefPubMedGoogle Scholar
• 67 Jung Y, McCall SJ, Li YX, Diehl AM. Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis. Hepatology 2007; 45 (5) 1091-1096
  CrossrefPubMedGoogle Scholar
• 68 Omenetti A, Popov Y, Jung Y , et al. The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. Gut 2008; 57 (9) 1275-1282
  CrossrefPubMedGoogle Scholar
• 69 Omenetti A, Syn WK, Jung Y , et al. Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production. Hepatology 2009; 50 (2) 518-527
  CrossrefPubMedGoogle Scholar
• 70 Tacke F, Luedde T, Trautwein C. Inflammatory pathways in liver homeostasis and liver injury. Clin Rev Allergy Immunol 2009; 36 (1) 4-12
  CrossrefPubMedGoogle Scholar
• 71 Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001; 104 (4) 487-501
  CrossrefPubMedGoogle Scholar
• 72 Del Villar K, Miller CA. Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer's disease brain and hippocampal neurons. Proc Natl Acad Sci U S A 2004; 101 (12) 4210-4215
  CrossrefPubMedGoogle Scholar
• 73 Sleiman PM, Flory J, Imielinski M , et al. Variants of DENND1B associated with asthma in children. N Engl J Med 2012; 366 (7) 672
  PubMedGoogle Scholar
• 74 Kitamura K, Nakamoto Y, Akiyama M , et al. Pathogenic roles of tumor necrosis factor receptor p55-mediated signals in dimethylnitrosamine-induced murine liver fibrosis. Lab Invest 2002; 82 (5) 571-583
  CrossrefPubMedGoogle Scholar
• 75 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
  CrossrefPubMedGoogle Scholar
• 76 Neuman M, Angulo P, Malkiewicz I , et al. Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis. J Gastroenterol Hepatol 2002; 17 (2) 196-202
  CrossrefPubMedGoogle Scholar
• 77 Pessach IM, Notarangelo LD. X-linked primary immunodeficiencies as a bridge to better understanding X-chromosome related autoimmunity. J Autoimmun 2009; 33 (1) 17-24
  CrossrefPubMedGoogle Scholar
• 78 Lleo A, Moroni L, Caliari L, Invernizzi P. Autoimmunity and Turner's syndrome. Autoimmun Rev 2012; 11 (6-7) A538-A543
  CrossrefPubMedGoogle Scholar
• 79 Selmi C, Invernizzi P, Zuin M, Podda M, Seldin MF, Gershwin ME. Genes and (auto)immunity in primary biliary cirrhosis. Genes Immun 2005; 6 (7) 543-556
  CrossrefPubMedGoogle Scholar
• 80 Selmi C, Invernizzi P, Miozzo M, Podda M, Gershwin ME. Primary biliary cirrhosis: does X mark the spot?. Autoimmun Rev 2004; 3 (7-8) 493-499
  CrossrefPubMedGoogle Scholar
• 81 Bogdanos DP, Smyk DS, Rigopoulou EI , et al. Twin studies in autoimmune disease: genetics, gender and environment. J Autoimmun 2012; 38 (2-3) J156-J169
  CrossrefPubMedGoogle Scholar
• 82 Invernizzi P, Alessio MG, Smyk DS , et al. Autoimmune hepatitis type 2 associated with an unexpected and transient presence of primary biliary cirrhosis-specific antimitochondrial antibodies: a case study and review of the literature. BMC Gastroenterol 2012; 12: 92
  CrossrefPubMedGoogle Scholar
• 83 Smyk DS, Rigopoulou EI, Lleo A , et al. Immunopathogenesis of primary biliary cirrhosis: an old wives' tale. Immun Ageing 2011; 8 (1) 12
  CrossrefPubMedGoogle Scholar
• 84 Smyk DS, Rigopoulou EI, Pares A , et al. Sex differences associated with primary biliary cirrhosis. Clin Dev Immunol 2012; 2012: 610504
  PubMedGoogle Scholar
• 85 Smyk DS, Rigopoulou EI, Pares A, Mytilinaiou MG, Invernizzi P, Bogdanos DP. Familial primary biliary cirrhosis: like mother, like daughter?. Acta Gastroenterol Belg 2012; 75 (2) 203-209
  PubMedGoogle Scholar
• 86 Svyryd Y, Hernández-Molina G, Vargas F, Sánchez-Guerrero J, Segovia DA, Mutchinick OM. X chromosome monosomy in primary and overlapping autoimmune diseases. Autoimmun Rev 2012; 11 (5) 301-304
  CrossrefPubMedGoogle Scholar
• 87 Lleo A, Battezzati PM, Selmi C, Gershwin ME, Podda M. Is autoimmunity a matter of sex?. Autoimmun Rev 2008; 7 (8) 626-630
  CrossrefPubMedGoogle Scholar
• 88 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
  CrossrefPubMedGoogle Scholar
• 89 Persani L, Bonomi M, Lleo A , et al. Increased loss of the Y chromosome in peripheral blood cells in male patients with autoimmune thyroiditis. J Autoimmun 2012; 38 (2-3) J193-J196
  CrossrefPubMedGoogle Scholar
• 90 Quintana-Murci L, Krausz C, McElreavey K. The human Y chromosome: function, evolution and disease. Forensic Sci Int 2001; 118 (2-3) 169-181
  CrossrefPubMedGoogle Scholar
• 91 Chueh FY, Leong KF, Cronk RJ, Venkitachalam S, Pabich S, Yu CL. Nuclear localization of pyruvate dehydrogenase complex-E2 (PDC-E2), a mitochondrial enzyme, and its role in signal transducer and activator of transcription 5 (STAT5)-dependent gene transcription. Cell Signal 2011; 23 (7) 1170-1178
  CrossrefPubMedGoogle Scholar
• 92 Noelle RJ, Nowak EC. Cellular sources and immune functions of interleukin-9. Nat Rev Immunol 2010; 10 (10) 683-687
  CrossrefPubMedGoogle Scholar
• 93 Merino R, Fossati L, Lacour M, Izui S. Selective autoantibody production by Yaa+ B cells in autoimmune Yaa(+)-Yaa- bone marrow chimeric mice. J Exp Med 1991; 174 (5) 1023-1029
  CrossrefPubMedGoogle Scholar
• 94 Subramanian S, Tus K, Li QZ , et al. A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc Natl Acad Sci U S A 2006; 103 (26) 9970-9975
  CrossrefPubMedGoogle Scholar
• 95 Fairhurst AM, Hwang SH, Wang A , et al. Yaa autoimmune phenotypes are conferred by overexpression of TLR7. Eur J Immunol 2008; 38 (7) 1971-1978
  CrossrefPubMedGoogle Scholar
• 96 Santiago-Raber ML, Kikuchi S, Borel P , et al. Evidence for genes in addition to Tlr7 in the Yaa translocation linked with acceleration of systemic lupus erythematosus. J Immunol 2008; 181 (2) 1556-1562
  CrossrefPubMedGoogle Scholar
• 97 Esteller M. Non-coding RNAs in human disease. Nat Rev Genet 2011; 12 (12) 861-874
  CrossrefPubMedGoogle Scholar
• 98 Katoh H, Zheng P, Liu Y. FOXP3: genetic and epigenetic implications for autoimmunity. J Autoimmun 2013; 41: 72-78
  CrossrefPubMedGoogle Scholar
• 99 Lu Q. The critical importance of epigenetics in autoimmunity. J Autoimmun 2013; 41: 1-5
  CrossrefPubMedGoogle Scholar
• 100 Wang Q, Selmi C, Zhou X , et al. Epigenetic considerations and the clinical reevaluation of the overlap syndrome between primary biliary cirrhosis and autoimmune hepatitis. J Autoimmun 2013; 41: 140-145
  CrossrefPubMedGoogle Scholar
• 101 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
  CrossrefPubMedGoogle Scholar
• 102 Gay S, Wilson AG. The emerging role of epigenetics in rheumatic diseases. Rheumatology (Oxford) 2014; 53 (3) 406-414
  CrossrefPubMedGoogle Scholar
• 103 Pillai S. Rethinking mechanisms of autoimmune pathogenesis. J Autoimmun 2013; 45: 97-103
  CrossrefPubMedGoogle Scholar
• 104 Costenbader KH, Gay S, Alarcón-Riquelme ME, Iaccarino L, Doria A. Genes, epigenetic regulation and environmental factors: which is the most relevant in developing autoimmune diseases?. Autoimmun Rev 2012; 11 (8) 604-609
  CrossrefPubMedGoogle Scholar
• 105 Selmi C, Cavaciocchi F, Lleo A , et al. Genome-wide analysis of DNA methylation, copy number variation, and gene expression in monozygotic twins discordant for primary biliary cirrhosis. Front Immunol 2014; 5: 128
  PubMedGoogle Scholar
• 106 Carrel L, Willard HF. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 2005; 434 (7031) 400-404
  CrossrefPubMedGoogle Scholar
• 107 Ozbalkan Z, Bagişlar S, Kiraz S , et al. Skewed X chromosome inactivation in blood cells of women with scleroderma. Arthritis Rheum 2005; 52 (5) 1564-1570
  CrossrefPubMedGoogle Scholar
• 108 Brix TH, Knudsen GP, Kristiansen M, Kyvik KO, Orstavik KH, Hegedüs L. High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity. J Clin Endocrinol Metab 2005; 90 (11) 5949-5953
  CrossrefPubMedGoogle Scholar
• 109 Uz E, Loubiere LS, Gadi VK , et al. Skewed X-chromosome inactivation in scleroderma. Clin Rev Allergy Immunol 2008; 34 (03) 352-355
  CrossrefPubMedGoogle Scholar
• 110 Ozcelik T. X chromosome inactivation and female predisposition to autoimmunity. Clin Rev Allergy Immunol 2008; 34 (03) 348-351
  CrossrefPubMedGoogle Scholar
• 111 Higuchi M, Horiuchi T, Kojima T , et al. Analysis of CD40 ligand gene mutations in patients with primary biliary cirrhosis. Scand J Clin Lab Invest 1998; 58 (5) 429-432
  CrossrefPubMedGoogle Scholar
• 112 Zheng Y, Rudensky AY. Foxp3 in control of the regulatory T cell lineage. Nat Immunol 2007; 8 (5) 457-462
  CrossrefPubMedGoogle Scholar
• 113 Padgett KA, Lan RY, Leung PC , et al. Primary biliary cirrhosis is associated with altered hepatic microRNA expression. J Autoimmun 2009; 32 (3-4) 246-253
  CrossrefPubMedGoogle Scholar
• 114 Qin B, Huang F, Liang Y, Yang Z, Zhong R. Analysis of altered microRNA expression profiles in peripheral blood mononuclear cells from patients with primary biliary cirrhosis. J Gastroenterol Hepatol 2013; 28 (3) 543-550
  CrossrefPubMedGoogle Scholar
• 115 Banales JM, Sáez E, Uriz M , et al. Up-regulation of microRNA 506 leads to decreased Cl-/HCO3- anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis. Hepatology 2012; 56 (2) 687-697
  CrossrefPubMedGoogle Scholar
• 116 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
  CrossrefPubMedGoogle Scholar
• 117 Ninomiya M, Kondo Y, Funayama R , et al. Distinct microRNAs expression profile in primary biliary cirrhosis and evaluation of miR 505-3p and miR197-3p as novel biomarkers. PLoS ONE 2013; 8 (6) e66086
  CrossrefPubMedGoogle Scholar
• 118 Qian C, Chen SX, Ren CL, Zhong RQ, Deng AM, Qin Q. [Abnormal expression of miR-let-7b in primary biliary cirrhosis and its clinical significance]. Zhonghua Gan Zang Bing Za Zhi 2013; 21 (7) 533-536
  PubMedGoogle Scholar
• 119 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
  CrossrefPubMedGoogle Scholar
• 120 Liu JZ, Hov JR, Folseraas T , et al; UK-PSCSC Consortium; International IBD Genetics Consortium; International PSC Study Group. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet 2013; 45 (6) 670-675
  CrossrefPubMedGoogle Scholar
• 121 Taş S, Avci O. Rapid clearance of psoriatic skin lesions induced by topical cyclopamine. A preliminary proof of concept study. Dermatology 2004; 209 (2) 126-131
  CrossrefPubMedGoogle Scholar
• 122 Feldmann M, Maini RN. Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med 2003; 9 (10) 1245-1250
  CrossrefPubMedGoogle Scholar
• 123 Braun J, Davis J, Dougados M, Sieper J, van der Linden S, van der Heijde D. ASAS Working Group. First update of the international ASAS consensus statement for the use of anti-TNF agents in patients with ankylosing spondylitis. Ann Rheum Dis 2006; 65 (3) 316-320
  CrossrefPubMedGoogle Scholar
• 124 Gisondi P, Girolomoni G. Biologic therapies in psoriasis: a new therapeutic approach. Autoimmun Rev 2007; 6 (8) 515-519
  CrossrefPubMedGoogle Scholar
• 125 Rutgeerts P, Vermeire S, Van Assche G. Biological therapies for inflammatory bowel diseases. Gastroenterology 2009; 136 (4) 1182-1197
  CrossrefPubMedGoogle Scholar