Genetic Contribution to the Pathogenesis of Primary Biliary Cholangitis.
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis [1, 2], is a liver-specific autoimmune disease characterized by female preponderance and destruction of intrahepatic bile ducts that often results in cirrhosis and hepatic failure [3-5]. The prevalence of PBC ranges from 20 to 40 cases per 100,000 persons [4-6], although the number of patients with PBC, specifically asymptomatic PBC, is on the rise due mainly to increased awareness and earlier detection by disease-specific antimitochondrial antibodies (AMAs). Ursodeoxycholic acid (UDCA) therapy is the most effective treatment for PBC and is recommended by most guidelines [7, 8]. The vast majority of patients with PBC show a favorable response to UDCA treatment despite some cases of disease progression via unknown mechanisms [9,10]. Genetic factors are considered to play a prominent role in disease onset as higher concordance rates in monozygotic twins than in dizygotic twins and familial clustering of patients with PBC has been demonstrated in family and population studies [11-16]. However, the etiology of this disease has yet to be conclusively clarified; PBC is presumed to be a multifactorial polygenic condition caused by allelic triggers and environmental factors in genetically susceptible individuals, although epigenetic mechanisms, such as instability of X chromosome gene expression, may also participate in the disease's female predominance [17-19].
In the present article, we summarize the literature on human leukocyte antigen (HLA) involvement in PBC onset and GWAS findings from North American, European, and Japanese populations to explore the disease pathways of PBC pathogenesis.
2. Associations between HLA and PBC Susceptibility
Many significant susceptibility single nucleotide polymorphisms (SNPs), such as CTLA4, TNF-[alpha], STAT4, PTPN22, and VDR, have been identified using candidate gene methods [20-24]. Among them, however, only HLA has consistently been associated with PBC in distinct patient cohorts across ethnicities.
Located on the most gene-dense genomic region on chromosomal position 6p21 , HLA genes are extremely polymorphic and play an essential role in numerous biologically and medically relevant processes. The products of the classical HLA class I (A, B, and C) and class II (DR, DQ, and DP) genes include cell-surface glycoproteins involved in the binding and presentation of self- or non-self-peptides to Tcell receptors (TCRs). Class I molecules present endogenous peptides derived from viruses to [CD8.sup.+] cytotoxic T cells, while class II molecules present processed peptides from exogenous pathogens to [CD4.sup.+] helper T cells. The extent of endogenous and exogenous peptide binding to HLA molecules depends on allelic polymorphisms. Additionally, both HLA class I and II molecules have functional roles in protein interactions, transcription regulation involved in the inflammatory response, and natural killer cell-cytokine interactions as part of innate immunity.
HLA polymorphisms have been extensively studied in immune-mediated diseases, revealing associations of particular alleles with ankylosing spondylitis (AS), Behcet's disease (BD), psoriasis, multiple sclerosis (MS), insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), narcolepsy, autoimmune hepatitis (AIH), and autoimmune pancreatitis (AIP) among others. Early investigations on associations between HLA polymorphisms and PBC were carried out more than a quarter-century ago . Based on these findings, subsequent cumulative studies have provided evidence that PBC is associated with DRB[1.sup.*] 08 as predisposing and DRB[1.sup.*]11 and DRB[1.sup.*]13 as protective alleles [28,38]. Li et al. conducted a meta-analysis to assess for relationships between HLA class II and disease susceptibility to PBC and demonstrated that HLA DR* 07 and *08 alleles were risk factors for PBC in certain populations, whereas DR* 11, *12, *13, and *15 alleles were protective factors .
Several key reports [26-28] on the association between HLA haplotype and PBC susceptibility or resistance are summarized in Table 1. HLA D[R.sup.*] 08 alleles caused disease susceptibility, while HLA DRB[1.sup.*]13 and [sup.*]11 alleles conferred disease protection in haplotype analyses across ethnicities. Both protective DRB[1.sup.*]11 and DRB[1.sup.*]13 alleles have also been implicated DRB[1.sup.*] 11 against hepatitis C , human papilloma , and human immunodeficiency  and DRB[1.sup.*]13 against hepatitis C , human papilloma , and human immunodeficiency  viruses along with malaria . Thus, one of the pathogenic mechanisms in PBC may be bacterial infection as these protective HLA class II alleles play a functional role in blocking the invasion of infectious agents.
However, individuals harboring the above haplotypes constitute only a minority of patients with PBC, suggesting that other candidate genes and environmental cues evoke PBC pathogenesis. Umemura et al.  reported the possibility that the distribution of DRB1 amino acid residues encoded by different HLA DRB1 alleles influenced the binding affinity to antigens, which might also be a predominant factor in PBC susceptibility.
3. GWAS on PBC
There have been extensive GWAS in patients with PBC, a number of which documenting significant associations with disease risk. To date, five GWAS [29-33], two Illumina immunochip studies [34, 35], and one genome-wide meta-analysis (GWMA)  on PBC have been performed on well-characterized cohorts in North American, European, and Japanese populations (Table 2). These investigations clarified that the HLA class II domain possessed the strongest association with disease susceptibility, particularly at the HLA-DRB1, HLA-DQA1,and HLA-DQB1 loci. However, HLA alone does not explain the entire genetic predisposition to PBC, mainly since 80-90% of patients with the disease do not carry the most common HLA susceptibility alleles. In this regard, other genes apart from HLA loci are suggested to contribute to disease development. At present, GWAS have identified 39 non-HLA loci predisposing to PBC at a genome-wide level of significance (Table 3).
The first GWAS  in a North American cohort identified a significant association of PBC with genetic variants at IL12A, encoding IL-12 p35, and IL12RB2, encoding IL-12 receptor [beta]2. Modest (p < 5.0 x [10.sup.-5]) genome-wide associations with disease risk for SNPs at the signal transducer and activator of transcription 4 (STAT4) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) loci were found as well. The second GWAS  confirmed the existence of additional risk loci, including interferon regulatory factor 5 (IRF5), transportin 3 (TNPO3), and SPIB encoding a transcription factor involved in B-cell receptor signaling and T-cell lineage decisions. A subsequent noteworthy GWAS from Japan showed that the IL12A and IL12RB2 loci were not significantly associated with PBC, but rather that the TNFSF15 and POU2AF1 genes constituted novel risk loci in Japanese patients with PBC along with other non-HLA loci, including IL7R, IKZF3, CD80, STAT4, and NFKB1. This discrepancy among ethnicities indicated important differences in the pathogenesis of PBC despite several common key molecules and pathways, such as the IL-12 pathway to induce Th1 polarization of [CD4.sup.+] T cells. Our body of evidence suggests that there maybe an inherited abnormality in immune regulation during PBC onset and perhaps an inability to suppress inflammatory attacks on small bile ducts once initiated.
It should be noted that Juran et al. identified risk-conferring epistatic interactions between IL12RB2 and IRF5 loci  as well as between CTLA4 and TNF[alpha] loci in the preGWAS era . Epistatic interactions between genes revealed by GWAS in the pathogenesis of PBC should be explored in future studies.
While gene associations are of considerable interest in the pathogenesis of PBC, virtually none have been translated into useful clinical testing. For instance, the importance of the IL-12 pathway in PBC onset has been highlighted in animal models and in the case of a child with a congenital IL-12 deficiency who developed PBC . Although antibodies or drugs targeting the IL-12 pathway would seem to be effective, clinical trials using ustekinumab, a human monoclonal antibody directed against IL-12 and IL-23, have failed to produce effects in phase II trials . One reason explaining the discrepancy between GWAS results and clinical testing may be that clinicians typically encounter patients who have already become complicated with cholestasis; in fact, the immunological destruction of cholangiocytes occurs in the very early stages of PBC. Thus, the mechanisms of disease progression should also be addressed to halt the deterioration of disease status and afford PBC patients an improved prognosis.
Lastly, it is particularly interesting that many genes implicated in PBC pathogenesis by GWAS have also been reported in other autoimmune diseases, such as SLE, systemic sclerosis (SSc), and Sjogren's syndrome (Table 3), suggesting a genetic overlap. Understanding the mechanisms involved in the onset and progression of certain autoimmune diseases may accordingly shed light on those in PBC.
4. Conclusions and Future Directions
The pathogenesis of PBC is incompletely understood but appears to involve genetic susceptibility and resistance alleles in HLA and other gene loci, with a possible overlap with several autoimmune diseases. It is also probable that genetically susceptible individuals develop PBC following environmental cues, leading to both adaptive and innate immune responses that result in portal inflammation and bile duct epithelial damage. In addition to susceptibility, the precise mechanisms of PBC progression should be addressed to improve patient prognosis and quality of life.
The authors declare that they have nothing to disclose regarding funding from industries or conflict of interests with respect to this manuscript.
The authors sincerely appreciate the financial support provided by Grants-in-Aid for Young Scientists (Kakenhi 16K21069) and the Promotion Project of Education, Research, and Medical Care from Shinshu University Hospital. They also thank Mr. Trevor Ralph for his English editorial assistance.
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Satoru Joshita, (1) Takeji Umemura, (1) Eiji Tanaka, (1) and Masao Ota
(1) Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
(2) Department of Legal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
Correspondence should be addressed to Satoru Joshita; email@example.com and Masao Ota; firstname.lastname@example.org
Received 18 October 2016; Accepted 12 January 2017; Published 1 February 2017
Academic Editor: Nancy Agmon-Levin
Table 1: HLA haplotype associations with PBC. Study Population HLA allele Susceptibility Umemura et al. Japanese DRB1*08:03-DQB1* 06:01  DRB1*04:05-DQB1* 04:01 Zhao et al. Chinese DRB1*08:03-DQB1* 06:01  DRB1*07:01-DQB1* 02:02 Donaldson et al. UK DRB1* 08:01-DQA1* 04* 01-DQB1* 04:02  Italian DRB1* 08:01-DQA1* 04* 01-DQB1* 04:02 Protective Umemura et al. Japanese DRB1*13:02-DQB1* 06:04  DRB1*11:01-DQB1* 03:01 Zhao et al. Chinese DRB1*12:02-DQB1* 03:01  Donaldson et al. UK DRB1*11:01-DQA1*05:01-DQB1* 03:01  Italian DRB1* 13:01-DQA1*01:03-DQB1* 06:03 Study p value OR (95% CI) Susceptibility Umemura et al. 0.000025 2.22 (1.53-3.20)  0.044 1.38 (10.2-1.87) Zhao et al. <0.0001 3.17 (1.91-5.23)  0.005 1.85 (1.20-2.83) Donaldson et al. 0.0027 2.9  0.0086 3.41 Protective Umemura et al. 0.00093 0.27 (0.12-0.60)  0.03 0.37 (0.15-0.88) Zhao et al. 0.015 0.43 (0.22-0.86)  Donaldson et al. 0.086 0.47  0.0041 0.28 Table 2: GWAS on PBC. Study Year Platform Patients Controls Hirschfield et al. 2009 Illumina HumanHap 370 1,031 2,713  Hirschfield et al. 2010 Illumina HumanHap 370 1,351 4,700  Liu et al. 2010 Illumina 610K 945 4,651  Mells et al. 2011 Illumina 660W-Quad 1,840 5,163  Nakamura et al. 2012 Asymetrix Axiom 1,274 1,091  Juran et al. 2012 Immunochip 2,426 5,731  Liu et al. 2012 Immunochip 2,861 8,514  Cordell et al. 2015 GWMA 2,764 10,475  Table 3: Non-HLA risk loci identified through GWAS as associated with PBC at the genome-wide level of significance. Chromosome Locus Study SNP OR p value [reference #] 1p31  rs72678531 1.61 2.47.E--38 1 1p36  rs3748816 1.33 3.15E-08 1q31  rs12134279 1.34 2.06E--14 2q12  rs12712133 1.14 5.19E--09 2 2q12  rs10186746 1.21 2.40E--05 2q32  rs10931468 1.50 2.35 E- 19 2q36  rs4973341 1.22 2.34E--10 3p24  rs1372072 1.20 2.28E--08 3 3q13  rs2293370 1.39 6.84E--16 3q25  rs2366643 1.35 3.92E--22 4 4p16  rs11724804 1.22 9.01E- 12 4q24  rs7665090 1.26 8.48E--14 5p13  rs6871748 1.30 2.26E--13 5 5q21  rs526231 1.15 1.14E-08 5q33  rs2546890 1.15 1.06E--10 6 6q23  rs6933404 1.18 1.27A--10 6q23  rs6920220 1.29 1.17.E--06 7 7p14  rs6974491 1.25 4.44E--08 7q32  rs35188261 1.52 6.52E--22 8 8q24  rs2608029 1.23 3.14E-06 9 9p32  rs4979462 1.57 1.85E--14 11q13  rs538147 1.23 2.06E--10 11 11q13  rs10898201 1.31 4.91E-06 11q23  rs4938534 1.38 3.27A--08 11q23  rs80065107 1.39 7.20E--16 12p13  rs1800693 1.27 1.18E- 14 12 12q24  rs11065979 1.20 2.87.E--09 12q24  rs7309325 1.26 2.54E--05 13 13q14 [34, 35] rs3862738 1.33 2.18E-08 14 14q24  rs911263 1.26 9.95E- 11 14q32  rs8017161 1.22 2.61E- 13 16 16p13  rs12708715 1.29 2.19E- 13 16q24  rs11117432 1.31 4.66E- 11 17 17q12  rs17564829 1.26 6.05E--14 17q21  rs17564829 1.25 2.15E-09 19p12  rs34536443 1.91 1.23E- 12 19 19p13  rs73003205 1.35 1.43E--05 19q13  rs3745516 1.46 7.97.E--11 22 22q13  rs2267407 1.29 1.29E- 13 Chromosome Locus Candidate Disease(s) with gene(s) shared risk loci 1p31 IL12RB2 BD 1 1p36 MMEL1 MS 1q31 DENND1B CD 2q12 IL1RL1, IL1RL2, 2 2q12 IL1RL1, IL1RL2, 2q32 STAT4, STAT1 RA, SLE, Sjogren's, IBD, SSc, BD 2q36 CCL20 3p24 PLCL2 RA 3 3q13 CD80 MS, SLE, Celiac 3q25 IL12A Celiac 4 4p16 DGKQ 4q24 NFKB1 UC 5p13 IL7R MS, UC 5 5q21 C5orf30 5q33 IL12B, LOC285626 6 6q23 OLIG3, TNFAIP3 6q23 OLIG3, TNFAIP3 7 7p14 ELMO1 RA, Celiac 7q32 IRF5 RA, SLE, SSc, UC 8 8q24 PVT1, GSDMC 9 9p32 TNFSF15 UC, CD 11q13 RPS6KA4 IBD 11 11q13 NADSYN1 11q23 POU2AF1 11q23 CXCR5, DDX6 RA, IBD, Celiac 12p13 TNFRSF1A, LTBR MS 12 12q24 SH2B3 RA, T1DM, Hyperthyroidism, Celiac 12q24 SH2B3 RA, T1DM, Hyperthyroidism, Celiac 13 13q14 TNFSF11 CD 14 14q24 RAD51B RA 14q32 TNFAIP2 16 16p13 CLEC16A, SOCS1 MS, UC, T1DM 16q24 IRF8 MS, IBD, RA, SSc 17 17q12 IKZF3 UC, CD, RA, T1DM 17q21 MAPT 19p12 TYK2 IBD, RA, SLE, psoriasis, T1DM 19 19p13 KIAA1683 19q13 SPIB 22 22q13 SYNGR1 CD, Crohn's disease; UC, ulcerative colitis; T1DM, type 1 diabetes mellitus.
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|Author:||Joshita, Satoru; Umemura, Takeji; Tanaka, Eiji; Ota, Masao|
|Publication:||Journal of Immunology Research|
|Date:||Jan 1, 2017|
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