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Genetic Contribution to the Pathogenesis of Primary Biliary Cholangitis.

1. Introduction

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 [25], 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 [37]. 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 [39].

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 [40], human papilloma [41], and human immunodeficiency [42] and DRB[1.sup.*]13 against hepatitis C [43], human papilloma [44], and human immunodeficiency [45] viruses along with malaria [44]. 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. [26] 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) [36] 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 [29] 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 [31] 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 [34] as well as between CTLA4 and TNF[alpha] loci in the preGWAS era [46]. 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 [47]. 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 [48]. 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.

http://dx.doi.org/10.1155/2017/3073504

Competing Interests

The authors declare that they have nothing to disclose regarding funding from industries or conflict of interests with respect to this manuscript.

Acknowledgments

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; joshita@shinshu-u.ac.jp and Masao Ota; otamasao@shinshu-u.ac.jp

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
[26]                                   DRB1*04:05-DQB1* 04:01

Zhao et al.         Chinese            DRB1*08:03-DQB1* 06:01
[27]                                   DRB1*07:01-DQB1* 02:02

Donaldson et al.       UK       DRB1* 08:01-DQA1* 04* 01-DQB1* 04:02
[28]
                    Italian     DRB1* 08:01-DQA1* 04* 01-DQB1* 04:02

Protective

Umemura et al.      Japanese           DRB1*13:02-DQB1* 06:04
[26]                                   DRB1*11:01-DQB1* 03:01

Zhao et al.         Chinese            DRB1*12:02-DQB1* 03:01
[27]

Donaldson et al.       UK        DRB1*11:01-DQA1*05:01-DQB1* 03:01
[28]                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)
[26]                0.044     1.38 (10.2-1.87)

Zhao et al.        <0.0001    3.17 (1.91-5.23)
[27]                0.005     1.85 (1.20-2.83)

Donaldson et al.    0.0027          2.9
[28]
                    0.0086          3.41

Protective

Umemura et al.     0.00093    0.27 (0.12-0.60)
[26]                 0.03     0.37 (0.15-0.88)

Zhao et al.         0.015     0.43 (0.22-0.86)
[27]

Donaldson et al.    0.086           0.47
[28]                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
[29]
Hirschfield et al.   2010   Illumina HumanHap 370    1,351      4,700
[30]
Liu et al.           2010       Illumina 610K         945       4,651
[31]
Mells et al.         2011    Illumina 660W-Quad      1,840      5,163
[32]
Nakamura et al.      2012      Asymetrix Axiom       1,274      1,091
[33]
Juran et al.         2012        Immunochip          2,426      5,731
[34]
Liu et al.           2012        Immunochip          2,861      8,514
[35]
Cordell et al.       2015           GWMA             2,764      10,475
[36]

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        [35]        rs72678531   1.61   2.47.E--38
1            1p36        [30]        rs3748816    1.33    3.15E-08
             1q31        [32]        rs12134279   1.34   2.06E--14
             2q12        [36]        rs12712133   1.14   5.19E--09

2            2q12        [34]        rs10186746   1.21   2.40E--05
             2q32        [32]        rs10931468   1.50   2.35 E- 19

             2q36        [36]        rs4973341    1.22   2.34E--10
             3p24        [32]        rs1372072    1.20   2.28E--08

3            3q13        [35]        rs2293370    1.39   6.84E--16
             3q25        [35]        rs2366643    1.35   3.92E--22

4            4p16        [36]        rs11724804   1.22   9.01E- 12
             4q24        [32]        rs7665090    1.26   8.48E--14
             5p13        [35]        rs6871748    1.30   2.26E--13

5            5q21        [36]         rs526231    1.15    1.14E-08
             5q33        [36]        rs2546890    1.15   1.06E--10

6            6q23        [36]        rs6933404    1.18   1.27A--10
             6q23        [34]        rs6920220    1.29   1.17.E--06

7            7p14        [32]        rs6974491    1.25   4.44E--08
             7q32        [35]        rs35188261   1.52   6.52E--22

8            8q24        [34]        rs2608029    1.23    3.14E-06

9            9p32        [33]        rs4979462    1.57   1.85E--14
             11q13       [32]         rs538147    1.23   2.06E--10

11           11q13       [34]        rs10898201   1.31    4.91E-06
             11q23       [33]        rs4938534    1.38   3.27A--08
             11q23       [35]        rs80065107   1.39   7.20E--16
             12p13       [35]        rs1800693    1.27   1.18E- 14

12           12q24       [35]        rs11065979   1.20   2.87.E--09

             12q24       [34]        rs7309325    1.26   2.54E--05

13           13q14     [34, 35]      rs3862738    1.33    2.18E-08

14           14q24       [35]         rs911263    1.26   9.95E- 11
             14q32       [32]        rs8017161    1.22   2.61E- 13

16           16p13       [35]        rs12708715   1.29   2.19E- 13
             16q24       [32]        rs11117432   1.31   4.66E- 11

17           17q12       [35]        rs17564829   1.26   6.05E--14
             17q21       [35]        rs17564829   1.25    2.15E-09
             19p12       [35]        rs34536443   1.91   1.23E- 12

19           19p13       [34]        rs73003205   1.35   1.43E--05
             19q13       [31]        rs3745516    1.46   7.97.E--11

22           22q13       [35]        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
Article Type:Report
Geographic Code:9JAPA
Date:Jan 1, 2017
Words:4083
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