Genetics and Epigenetics of Primary Biliary Cirrhosis Marco Carbone, MD2,3

Ana Lleo, MD, PhD1

1 Liver Unit and Center for Autoimmune Liver Diseases, Humanitas

Clinical and Research Center, Rozzano (MI), Italy 2 Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom 3 Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom 4 Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, California

Pietro Invernizzi, MD, PhD1,4

Address for correspondence Pietro Invernizzi, MD, PhD, Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via A. Manzoni 56, 20089 Rozzano (MI), Italy (e-mail: [email protected]).

Semin Liver Dis 2014;34:255–264.



► primary biliary cirrhosis ► genome-wide association study ► sex chromosomes ► immune-related pathways ► novel drugs

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.

Primary biliary cirrhosis (PBC) is considered a paradigmatic model of organ-specific autoimmune diseases characterized by loss of tolerance, production of a multilineage immune response to mitochondrial and nuclear proteins, inflammation and progressive destruction of intermediate intrahepatic small ducts leading in some patients to fibrosis, cirrhosis, and ultimately liver transplantation or death.1–3 Primary biliary cirrhosis is a rare disease with population-based studies indicating a wide range in yearly incidence (0.33–5.8/ 100,000) and point prevalence (1.91–40.2/100,000) rates.3 The recent development of animal models of PBC allows for the elucidation of many aspects of the pathogenesis of this autoimmune disease,4,5 including rigorous definitions of the serum signatures of antimitochondrial antibodies (AMAs) and disease-specific antinuclear autoantibodies (ANAs), as well as the definition of autoreactive T-cell responses and their asso-

Issue Theme Primary Biliary Cirrhosis; Guest Editor, Pietro Invernizzi, MD, PhD

ciation with some immunological signaling pathways, such as tumor necrosis factor (TNF) and nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB). The autoimmune nature of PBC also suggests a striking female predominance; epidemiological data indicate that family members of patients have an increased risk of developing PBC or other autoimmune disorders. Primary biliary cirrhosis can be diagnosed with confidence in patients with an otherwise unexplained elevation of alkaline phosphatase and gamma-glutamyl transferase and presence of AMAs and PBC-specific ANAs. A liver biopsy is not essential for the diagnosis of PBC, but is recommended because it allows one to assess the activity and stage of the disease.6 The only approved therapy for PBC is ursodeoxycholic acid (UDCA), an hydrophobic bile acid with protective effects on injured cholangiocytes mainly due to its ability to induce ductular alkaline choleresis.

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0034-1383725. ISSN 0272-8087.

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Ilaria Bianchi, MD, PhD1

Genetics and Epigenetics of Primary Biliary Cirrhosis

Bianchi et al.

Although familial occurrence and monozygotic twins’ concordance have suggested a strong heritability in PBC, no specific candidate genes have been identified. For decades, the only exception was a weak association with the DRB108 allele, a class II human leukocyte antigen (HLA), and two additional protective associations with the HLA DRB111 and DRB113 alleles.7–9 In the last few years, interest in HLA genes has grown significantly10 thanks to the genome-wide association studies (GWASs) and illumina immunoarray- (immunochip) association studies which demonstrated that the major component of the genetic architecture of this disease are within the HLA region.11–16 Unfortunately, the reasons why specific HLA alleles increase or reduce the risk for PBC development remains unclear.

Similar to many genetically complex diseases, such as rheumatoid arthritis, multiple sclerosis, and Crohn disease, recent high-throughput genetic studies in PBC have also identified dozens of novel disease-associated non-HLA variants.11–16 Overall, the non-HLA risk alleles were found in conjunction with genes related to immune functions (►Table 1), with important contributions from several immune pathways—these latter ranging from the antigen presentation and T-cell differentiation (class II HLA, IL12, IL12R, IL7R, CD80, STAT4, TYK2, SOCS1), the differentiation of myeloid cell lineage (IRF5, IRF8, SPIB, and IL-7R), to the B-cell function (SPIB, PLC-L2, IRF8, PLC-L2, CXCR5, IKZF3).17,18 These genetic variants are not specifically involved in one unique function.

Table 1 Nonhuman leukocyte antigen risk loci identified in at least one high-throughput genetic study of primary biliary cirrhosis (PBC) Locus


Odds ratio

P value

Candidate gene

Diseases sharing risk loci with PBC








































MS, CeD, Vit

















































































































































Abbreviations: CD, Crohn disease; CeD, celiac disease; MS, multiple sclerosis; PS, psoriasis; RA, rheumatoid arthritis; SARC, sarcoidosis; SNP, singlenucleotide polymorphism; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; T1DM, diabetes mellitus type 1; UC, ulcerative colitis; VIT, vitiligo. a For each locus, results are from the study with strongest evidence of association. Seminars in Liver Disease

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Genetic factors in PBC are further suggested by a strong female preponderance and a higher risk for disease development in female relatives of PBC patients.19–30 It has been suggested that this may be at least partially related to sex chromosome defects because many genes involved in immunological tolerance are located on the X chromosome.30–35 Although high-throughput genetic studies seem to exclude the presence of genetic aberrancies of the X chromosome in PBC, some recent data are disclosing a role for epigenetic modifications of the regulatory mechanisms of specific Xlinked genes.36,37 Epigenetic modifications such as DNA methylation may explain the environmental influence on individual susceptibility to PBC; further studies are needed to fully understand their role in the pathogenesis and female preponderance of PBC.38 In this review, we will mainly focus on the recent progress obtained with high-throughput genetic studies and studies of sex chromosomes and epigenetic abnormalities, and on how these data may transform the landscape of PBC research as well as our daily clinical practice with PBC patients.

Highlights from High-Throughput Genetic Studies The advent of genome-wide association technology has changed the landscape of genetics research in PBC, as well as in many other complex diseases, such as inflammatory bowel disease39 and diabetes.40 Genome-wide association studies allows for the identification of common genetic variants in a nonbiased fashion, based on the assumption that at least part of the genetic factors in many common diseases are attributable to a small number of common allelic variants present in more than 5% of the general population.41 These studies generally analyze millions of common genetic variants in both known and unknown genes or regulatory regions, require a large sample size to avoid false-positive findings and because of the low effect size of most disease variants (odds ratios ¼ 1.1–1.4),42 and have to include a replication of strongest associations in independent casecontrol panels. Large and well-characterized patient cohorts for genetic studies of PBC have been recently established in Europe, North America, and Japan, and four GWAS11–14 and two iCHIP-association studies15,16 revealed dozens of PBC-associated loci (►Table 1). These studies have provided important insights into the allelic architecture of PBC, and have shown that most of these genetic variants are not specifically involved in one unique function, but play an important role in several different immune pathways. For instance, IL-7R has a role in myeloid cell differentiation,43 but it also controls thymic CD8-lineage specification and peripheral naive Tcell homeostasis; it is also involved in the induction of Tcell activation.44 These studies also highlighted the considerable overlap of genetic susceptibility factors between PBC and several clinically associated autoimmune disorders. The identification of candidate genes at pleiotropic loci suggests that common pathways are involved in the pathogenesis of PBC as of other clinically associated disorders. These observations

Bianchi et al.

suggest that although distinct mechanisms might predispose to a particular phenotype/disease, there are unique immunologic pathways underling autoimmunity that should be targeted with novel drugs. Finally, as one of the major goals of high-throughput genetic studies is the identification of key pathways implicated in the pathogenesis of PBC, these studies could help to reveal novel therapeutic targets for this liver disease. Indeed, in PBC there is still a gap between our basic knowledge of the disease and novel therapeutic approaches. Ursodeoxycholic acid has been the only drug approved for PBC in the last two decades; however, a large number of new biologics merit further investigation in this disease to show their safety and efficacy.45 This is especially important because up to 40% of PBC patients do not respond to UDCA.1 Some of the pathways that may have therapeutic implications in PBC are reported below and are listed in ►Table 2.

Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells Loci containing genes involved in activation of NF-κB were identified by two GWASs in PBC13,14; in particular, the NFKB1 gene itself and genes in the NF-κB activation pathways such as CD80, TNFRSF1A, and RPS6KA4. Nuclear factor kappa-lightchain-enhancer of activated B cells is a well-known transcription factor able to regulate expression of a large number of genes involved in the immune response. Interestingly, NF-κB is highly activated in many other autoimmune disorders such as rheumatoid arthritis and asthma.46 Growing evidence indicates that coinhibitory molecules, such as CD80, have a key protective role in autoimmunity. One of the most largely characterized inhibitory pathways for the activation of T cells is the CD80/CD86:CD28/CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) pathway.47,48 CD28 is a cell-surface protein constitutively expressed on both naïve and activated T lymphocytes; CD80 and CD86 are expressed on antigen-presenting cells. However, CD80 is little expressed on resting antigen-presenting cells and is upregulated only with prolonged interaction with T cells, whereas CD86 is constitutively expressed and can be rapidly upregulated on antigen-presenting cells. For this reason, CD86 is mainly involved in rapid and initial T-cell activation, whereas CD80 plays a key role in maintaining immune responses to chronic inflammation. The activation of T lymphocytes upregulates the expression of CTLA-4 (CD152), with consequent negative signal and inhibition and termination of T-cell responses. With the aim of new drug development, a fusion protein expressing the extracellular domain of CTLA-4 and the constant region of IgG has been created to block the interaction between CD28 and CD80-CD86; because CTLA-4 binds CD86 and CD80 with much higher affinity than CD28 does,34 it is expected that this fusion protein would mostly inhibit T cells that respond to self-antigens without affecting resting lymphocytes that recognize other antigens. The efficacy of this CTLA-4 Ig (abatacept) has already been preclinically evaluated with encouraging results in several animal models, including PBC models.49 After these early in vivo studies, abatacept was demonstrated to be effective in a broad spectrum of Seminars in Liver Disease

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Genetics and Epigenetics of Primary Biliary Cirrhosis

Genetics and Epigenetics of Primary Biliary Cirrhosis

Bianchi et al.

Table 2 Molecular pathways identified in high-throughput genetic studies of primary biliary cirrhosis Pathways



Diseases in which inhibitors of these pathways have been evaluated


NF-κB regulates the expression of many genes involved in the immune response. NF-κB coinhibitory molecules are important in loss of tolerance. The CD80/CD86-CTLA-4 pathway is a key inhibitory pathway for activation of T cells

Anti-CD80 (abatacept)

Psoriasis52 Rheumatoid arthritis50,51


IL-12 stimulates the Th1-type immune response, thus contributing to loss of tolerance in many models of autoimmunity; IL-23 is essential for the differentiation of Th17 cells

Anti-IL-12/IL-23 (ustekinumab)

Crohn disease58,59 Psoriasis60

Hedgehog signaling

Key pathway in the response to cholestatic damage

Hedgehog-inhibitor (cyclopamine)


Phosphatidylinositol signaling

Crucial pathway for self-tolerance maintenance



Recent evidence indicates a dualistic, immunosuppressive and proinflammatory role for TNF in autoimmune conditions

Anti-TNF (infliximab, golimumab, etanercept, adalimumab, certolizumab)

__ Rheumatoid arthritis122 Ankylosing spondylitis123 Psoriasis124 Crohn disease125

Abbreviations: IL, interleukin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; TNF, tumor necrosis factor.

patients with rheumatoid arthritis from early stage to refractory diseases who are resistant to other therapies such as TNF blockers50,51 and in a phase I trial in patients with psoriasis.52 To block the costimulation between T lymphocytes and antigen-presenting cells through CD80 is clearly an important therapeutic approach for the treatment of PBC with incomplete UDCA response.

Interleukin 12 (IL-12)/IL-23 T-cell differentiation is another pathway suggested to have a role in the development of the disease by loci identified in GWAS. Th1 immune responses have been implicated in the underlying pathogenic mechanisms of most autoimmune diseases53 and are clearly involved in the development of autoreactive T cells. This is consistent with the role of the pyruvate dehydrogenase complex-specific autoreactive Th1 cells in the immunopathogenesis of PBC.54 It is known that anti-interleukin-12 (IL-12) signaling together with the IL-12 driven interferon-γ production, promotes Th1 immune response and loss of tolerance by differentiating naïve T cells to Th1 lymphocytes.55 Genome-wide association studies of PBC disclosed three loci containing genes involved in IL-12 signaling: the signal transducer and activator of the transcription (STAT4) gene13 and the genes IL12A, IL12RB211–13 codifying the subunit p35 of the IL-12, and the chain IL12Rβ2 of the IL-12 receptor, respectively.56 Studies conducted in an animal model of PBC by Gershwin’s group have clearly showed a role for the IL-12 pathway in this disease.57 Seminars in Liver Disease

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Several monoclonal antibody and inhibitors of p40, a subunit of the IL-12 receptor, have been developed and multiple clinical trials have shown therapeutic benefit in Crohn disease58,59 and psoriasis.60 The differentiation of Th17 cells involves not only the p40 subunit of IL-12 receptor, but also a component of the dimeric cytokine IL-23; pilot studies are under way to test the safety and efficacy of the human monoclonal anti-IL-12/IL-23 in PBC patients (ClinicalTrials. gov identifier: NCT01389973). Nevertheless, several questions remain and additional studies are needed. In particular, we need to clarify the crosstalk between IL-12 and IL-23 signaling pathways to better define the specific IL12A and IL12RB2 alleles conferring risk for PBC by means of further genetic association studies and sequencing studies, and to elucidate the relative contributions of Th17, Treg cells, and other immunocellular subpopulations to PBC by in vivo experiments. Finally, specific studies should be performed to understand the role for IL-35 because the cytokine IL-35 and its receptor include IL-12 p35 and IL-12Rβ2 among their subunits. The final goals of these studies should be to develop a novel therapy with a better outcome for patients with PBC.

Phosphatidylinositol Signaling and Hedgehog Signaling Pathways The phosphatidylinositol signaling system pathway is a key component of the adaptive immune response and is essential to maintaining self-tolerance as it is known to mediate the

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effects of TNF-α on NF-kB activation.61–63 Pathway analysis of the Canadian and Italian GWAS PBC cohorts have highlighted the possible involvement of this pathway in PBC, thus supporting the TNF hypothesis.61,62 This same study also suggested the involvement in the genetic architecture of PBC of the hedgehog (Hh) signaling system, a group of secreted proteins with a role in adult stem cell proliferation and organogenesis.64–66 Hh signaling has been widely characterized in PBC. In PBC, Hh signaling has been described as involved in the ductular response to cholestasis, characterized by proliferation of cholangiocytes and myofibroblastic cells.67 Hh signaling was found to promote the survival of biliary epithelial cells68 its activation is associated with increased ductular cell expression of proinflammatory genes, such as the gene producing Cxcl16, and in chemotaxis of the natural killer (NK) T cell toward cholangiocytes.69 Although preliminary, these data show that Hh signaling promotes the survival of potential hepatic progenitor cells and indicate that it is an important protective factor within the inflamed and damaged liver. The Hh signaling pathway may well represent a novel therapeutic target to promote cell proliferation and tissue repair in PBC and possibly other chronic liver diseases.

Tumor Necrosis Factor-α Tumor necrosis factor-α is known to play an important role in liver homeostasis by activating several intracellular pathways that determine the fate of hepatocytes.70 In particular, the TNF-α pathway is largely involved in the induction of apoptosis and activation of NF-kB signaling, which is proinflammatory and antiapoptotic.71 In PBC, GWASs identified several loci-containing genes in TNF-α signaling pathways such as TNFAIP2,13,14 TNFRSF1A, and DENND1B.13 Interestingly, DENND1B interacts directly with TNFRSF1A, one of two receptors for TNF-α,72 and was found to be associated with asthma.73 Knockout mice for the TNFRSF1A gene show milder liver fibrosis when compared with wild-type mice treated with a potent chemical that induces liver injury.74 We have shown that macrophages from PBC patients produce TNF-α when stimulated with apoptotic bodies from cholangiocytes and serum AMA.75 In addition, serum levels of TNF-α correlate with disease stage in PBC.76 Finally, the pathway analysis of the Italian GWAS cohort identified the TNF signaling pathway by applying a “self-contained” GWAS pathway analysis method (the linear combination test [LCT]).17 All these findings clearly indicate a key role for TNF-α in the pathogenesis of PBC and suggest the use of anti-TNF-α agents, currently accepted drugs for several autoimmune and inflammatory diseases, for the treatment of PBC.

The Genetics of Sex Chromosomes Primary biliary cirrhosis is characterized by a female preponderance and a higher risk for disease development in female relatives of patients with PBC, but the reason is still unclear. Links between the X chromosome and immunity have been strengthened by clinical data, such as X-linked immunodeficiencies,77 and the presence of many autoimmune features

Bianchi et al.

and autoimmune diseases in patients with Turner syndrome.78 In the last decade, several major defects in sex chromosomes of patients with PBC were reported.31,32,79–81 Our group evaluated the frequency of X monosomy by fluorescence in situ hybridization of peripheral leukocytes in 100 female patients with PBC, 50 patients with chronic hepatitis C, and 50 healthy women and showed that women with PBC have an enhanced frequency of monosomy X compared with controls31 and that the frequency of monosomy X increased with age. This major genetic defect may contribute to the explanation of why PBC occurs predominantly in middle-aged women and is absent in the pediatric age.82–85 We also noted that X monosomy was a feature of systemic sclerosis and autoimmune thyroid disease, which are often found to be concomitant in PBC patients,32 but not of other autoimmune disease such as systemic lupus erithematosus.33 Our group also showed that X monosomy was more frequent in peripheral T and B lymphocytes than blood cells from the innate immune system such as monocytes and NK cells.31,32 Importantly, these findings were confirmed by others in Reynold syndrome, a laminopathy with combined PBC and progressive systemic sclerosis (SSc).86 In particular, X monosomy was found in 12% of patients with Reynold syndrome, 10% in PBC, 9% in SSc, and 6% in age-matched healthy controls.86 X-chromosome defects are more frequent in women with late-onset autoimmune disease.31,32,87 In PBC not only X-chromosome loss occurred more frequently but in a preferential fashion,88 further supporting the critical involvement of X-chromosome gene products in the disease and its female preponderance. It is still unknown the origin of the remaining X chromosome, as imprinting may also play a role in PBC development.88 In a more recent study, we also demonstrated that Ychromosome loss is higher in PBC males compared with healthy male controls, and that this phenomenon increases with aging.35 This confirms the existence of an analogous mechanism in the male population to previously identified X haploinsufficiency in female patients with organ-specific autoimmune disease. It is possible that the Y chromosome loss causes an imbalance for the alleles shared with X chromosomes as well as the loss of one X chromosome might lead to the haploinsufficiency of X-linked loci, thus escaping X-chromosome inactivation processes. The role of the Y chromosome in immunology and specifically in autoimmunity is still debated, but because a similar major genetic defect was found in male with autoimmune thyroiditis,89 it is possible that this commonality might represent a relevant feature in the etiopathogenesis of autoimmune diseases that should be further investigated. The Y chromosome does not contain vital genes because females do not have it. In particular, the Y chromosome harbors a limited number of Xchromosome homologues, mainly located at the pseudoautosomal regions, potentially relevant for the immune function.90 Among others, the interleukin receptors IL3RA and IL9R are possible candidates. IL3 might be implicated in the intracellular interaction between STAT5 molecules and PDCE2, the autoantigen in PBC,91 whereas imbalances of IL9R might have an effect on the suppressive T-cell compartment, Seminars in Liver Disease

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Genetics and Epigenetics of Primary Biliary Cirrhosis

Genetics and Epigenetics of Primary Biliary Cirrhosis

Bianchi et al.

being expressed by T cells.92 Another Y-chromosome gene that might be implicated in PBC pathogenesis and autoimmunity is the Y-linked autoimmune acceleration (Yaa)93 because the Yaa translocation from the telomeric end of the X chromosome onto the Y chromosome94 is known to cause this gene overexpression,95 and a consequent Yaa-mediated acceleration of lupus-like disease.96 Based on these data, it is possible that translocation of other X-linked genes to the Y chromosome mighty contribute to the initiation and perpetuation of PBC and autoimmunity.

Epigenetic Abnormalities in Primary Biliary Cirrhosis Epigenetics include any heritable and functional relevant changes in gene activity that are not caused by changes in the nucleotide sequence. There are several types of epigenetic mechanisms, although only four are generally accepted to be examples of epigenetics: (1) posttranslational modifications of the amino acids that make up histone tails of nucleosomes (i.e., methylation, acetylation, ubiquitination, etc.), (2) addition of methyl groups to the DNA to convert certain cytosine residues to 5-methylcytosine, (3) remodeling of chromatin by complexes of proteins that can enhance or suppress gene expression, and (4) silencing of gene expression by small noncoding RNA transcripts such as microRNA.97 The role of epigenetics in loss of tolerance and in the pathogenesis of rheumatic and autoimmune diseases, such as systemic lupus erythematosus, has been extensively described.98–102 Based on much evidence, it has been suggested that the lack of concordance in monozygotic twins in autoimmune diseases indicates that epigenetic factors are important in determining the susceptibility to autoimmunity besides environmental factors.81,103,104 On the contrary, in PBC only few studies are available on epigenetic factors,99 but these scanty data are disclosing a key role of epigenetic abnormalities in the disease.36,88,105 The studies on epigenetic abnormalities in PBC started about 10 years ago and focused on X chromosomes. Indeed, women are functional mosaics for X-linked genes and most genes on one of their two X chromosomes are silenced by mean of a DNA methylation process leading to an X-chromosome inactivation (XCI), although up to 15% of genes can escape XCI. This process is necessary to achieve equivalent dosage of X-linked gene products between males and females.106 In addition, it has been shown that up to 10% of total X-linked genes manifest variable XCI patterns in different individuals.106 Interestingly, it has been shown that women affected with several autoimmune diseases that are concomitant with PBC, such as SSc, autoimmune thyroid diseases, and Sjögren syndrome, manifest a skewed X inactivation in their peripheral blood cells.107–110 For these reasons, we set out to determine the mechanism of XCI in 166 female PBC patients and 266 age-matched controls, consisting of both healthy subjects and patients with liver disease, but we failed to find a preferential inactivation in PBC.88 It should be noted, however, that only this latter study accounted for more than one locus, whereas previous reports only investigated the androgen receptor methylation that poorly represents XCI. Seminars in Liver Disease

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More recently, Mitchell et al36 analyzed 125 variable Xchromosome inactivation status genes in peripheral blood mRNA and DNA from monozygotic discordant and concordant pairs. Consistently downregulated genes included CLIC2 and PIN4 in the twin with PBC, which was not found in the healthy twin or in control subjects.36 These data suggest that the possible mechanisms by which epigenetic factors influence PBC onset are likely much more complex than a simple X-linking of candidate genes.3,35,36,81 The interaction of CD40 and CD40L plays a key role in CD4þ T-cell priming, B-cell terminal maturation, and immunoglobulin class-switch recombination. Genetic defects in the CD40L gene, a gene located on the X chromosome, cause an immunodeficiency with elevated serum IgM levels.77 No gene mutations were detected in cDNA of CD40L from PBC patients by reverse-transcription polymerase chain reaction singlestrand conformation polymorphism (RT-PCR-SSCP) technique.111 Lleo et al have recently demonstrated significantly lower levels of DNA methylation of the CD40L promoter in CD4 þ T cells from PBC patients compared with controls, and more importantly, a decreased methylation inversely correlated with levels of serum IgM in PBC patients.37 The finding of a decreased DNA methylation of the CD40L promoter together with the absence of genetic defects of the CD40L gene in patients with PBC strongly suggests that environmental factors rather than genetics play a key role in the pathogenesis of elevated serum IgM in PBC. Other candidate immune-related genes of the X chromosome might have similar epigenetic defects in PBC and should be investigated in future studies. For example, the Foxp3 gene, which localizes in the short arm of the X chromosome, is important for T cells with regulatory functions; its deficiency leads to a highly aggressive and often fatal multiorgan autoimmune disease.112 Abnormalities in microRNAs expression are another epigenetic factor recently evaluated in PBC. MicroRNAs are known to play a vital role in the regulation of various aspects of immune function and in the development of autoimmune disease. It has been first shown that PBC is associated with altered expression of 35 hepatic microRNAs.113 In a subsequent study, 17 microRNAs are differentially expressed in peripheral blood mononuclear cells from patients with PBC.114 Although other microRNAs, such as miR-506, miR2, miR-let-7b, miR-505–3p, and miR-197–3p, were found to be associated with PBC,115–118 the precise role of microRNA in PBC remains unclear.

Conclusion Current evidence suggests a prominent role for genetic and epigenetic abnormalities in the development of PBC. With the application of genome-wide technology, HLA was confirmed as the strongest association in PBC and many other risk loci have been identified, including IL12A, IL12RB2, IRF5-TNPO3, STAT4, MMEL1, SPIB, 17q12.21, and CTLA-4. High throughput efforts to sequence exomes and genomes and the advent of deep sequencing have identified several pathways (i.e., TNF signaling, apoptosis, and antigen processing and

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Genetics and Epigenetics of Primary Biliary Cirrhosis

Acknowledgments MC is supported in part by the Dame Sheila Sherlock EASL Fellowship Program of the European Association for the Study of the Liver (EASL). AL and PI are supported in part by the National Institutes of Health (NIH) grant #DK091823– 01A1.

13 Mells GF, Floyd JA, Morley KI, et al; UK PBC Consortium; Wellcome






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presentation) that might contribute to the genetic predisposition to PBC. In addition, major sex chromosome defects and loss of epigenetic controls are also disclosing mechanisms underlying the PBC susceptibility alternative to DNA defects. However, it remains unclear the real effects of these epigenetic and genetic abnormalities in PBC; additional studies are still needed to clarify the involved effector mechanisms. Dedicated studies are needed to understand the precise relationship between genetic and epigenetic risk factors and therapy response, clinical progression, and symptoms. To translate this knowledge into direct benefits for PBC patients (mainly the development of rational, disease-specific, novel therapies) will require interaction among different biomedical disciplines, including molecular biology, genomics, clinical medicine, bioinformatics, and pharmacology.

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Genetics and epigenetics of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) has been considered a multifactorial autoimmune disease presumably arising from a combination of environmental and gen...
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