Journal of Immunology Research
Volume 2017 (2017), Article ID 3073504, 6 pages
https://doi.org/10.1155/2017/3073504

Review Article

Genetic Contribution to the Pathogenesis of Primary Biliary Cholangitis

Satoru Joshita,¹ Takeji Umemura,¹ Eiji Tanaka,¹ and Masao Ota²

¹Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
²Department 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

Copyright © 2017 Satoru Joshita et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Formerly termed primary biliary cirrhosis, primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease characterized by the presence of antimitochondrial antibodies. Ursodeoxycholic acid (UDCA) therapy is the most effective and approved treatment for PBC and leads to a favorable outcome in the vast majority of cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades. Individuals in different geographic regions of the world may have varying susceptibility alleles that reflect indigenous triggering antigens. In this review, we describe the influence of HLA alleles and other gene polymorphisms on PBC along with the results of genome-wide association studies (GWAS) on this disease.

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-a, 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 T-cell receptors (TCRs). Class I molecules present endogenous peptides derived from viruses to CD8⁺ cytotoxic T cells, while class II molecules present processed peptides from exogenous pathogens to CD4⁺ 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), Behçet’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 DRB1 08 as predisposing and DRB1 11 and DRB1 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 DR 08 alleles caused disease susceptibility, while HLA DRB1 13 and 11 alleles conferred disease protection in haplotype analyses across ethnicities. Both protective DRB1 11 and DRB1 13 alleles have also been implicated DRB1 11 against hepatitis C [40], human papilloma [41], and human immunodeficiency [42] and DRB1 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.

Table 1: HLA haplotype associations with PBC.

Study
Population
HLA allele
value
OR (95% CI)

Susceptibility

Umemura et al. [26]
Japanese
DRB108:03-DQB106:01
0.000025
2.22 (1.53–3.20)

DRB104:05-DQB104:01
0.044
1.38 (10.2–1.87)

Zhao et al. [27]
Chinese
DRB108:03-DQB106:01
<0.0001
3.17 (1.91–5.23)

DRB107:01-DQB102:02
0.005
1.85 (1.20–2.83)

Donaldson et al. [28]
UK
DRB108:01-DQA10401-DQB104:02
0.0027
2.9

Italian
DRB108:01-DQA10401-DQB104:02
0.0086
3.41

Protective

Umemura et al. [26]
Japanese
DRB113:02-DQB106:04
0.00093
0.27 (0.12–0.60)

DRB111:01-DQB103:01
0.03
0.37 (0.15–0.88)

Zhao et al. [27]
Chinese
DRB112:02-DQB103:01
0.015
0.43 (0.22–0.86)

Donaldson et al. [28]
UK
DRB111:01-DQA105:01-DQB103:01
0.086
0.47

Italian
DRB113:01-DQA101:03-DQB106:03
0.0041
0.28

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).

Table 2: GWAS on PBC.

Study
Year
Platform
Patients
Controls

Hirschfield et al. [29]
2009
Illumina HumanHap 370
1,031
2,713

Hirschfield et al. [30]
2010
Illumina HumanHap 370
1,351
4,700

Liu et al. [31]
2010
Illumina 610K
945
4,651

Mells et al. [32]
2011
Illumina 660W-Quad
1,840
5,163

Nakamura et al. [33]
2012
Affymetrix Axiom
1,274
1,091

Juran et al. [34]
2012
Immunochip
2,426
5,731

Liu et al. [35]
2012
Immunochip
2,861
8,514

Cordell et al. [36]
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
reference
SNP
OR
value
Candidate gene(s)
Disease(s) with shared risk loci

1
1p31
[35]
rs72678531
1.61

IL12RB2
BD

1p36
[30]
rs3748816
1.33

MMEL1
MS

1q31
[32]
rs12134279
1.34

DENND1B
CD

2
2q12
[36]
rs12712133
1.14

IL1RL1, IL1RL2,

2q12
[34]
rs10186746
1.21

IL1RL1, IL1RL2,

2q32
[32]
rs10931468
1.50

STAT4, STAT1
RA, SLE, Sjögren’s, IBD, SSc, BD

2q36
[36]
rs4973341
1.22

CCL20

3
3p24
[32]
rs1372072
1.20

PLCL2
RA

3q13
[35]
rs2293370
1.39

CD80
MS, SLE, Celiac

3q25
[35]
rs2366643
1.35

IL12A
Celiac

4
4p16
[36]
rs11724804
1.22

DGKQ

4q24
[32]
rs7665090
1.26

NFKB1
UC

5
5p13
[35]
rs6871748
1.30

IL7R
MS, UC

5q21
[36]
rs526231
1.15

C5orf30

5q33
[36]
rs2546890
1.15

IL12B, LOC285626

6
6q23
[36]
rs6933404
1.18

OLIG3, TNFAIP3

6q23
[34]
rs6920220
1.29

OLIG3, TNFAIP3

7
7p14
[32]
rs6974491
1.25

ELMO1
RA, Celiac

7q32
[35]
rs35188261
1.52

IRF5
RA, SLE, SSc, UC

8
8q24
[34]
rs2608029
1.23

PVT1, GSDMC

9
9p32
[33]
rs4979462
1.57

TNFSF15
UC, CD

11
11q13
[32]
rs538147
1.23

RPS6KA4
IBD

11q13
[34]
rs10898201
1.31

NADSYN1

11q23
[33]
rs4938534
1.38

POU2AF1

11q23
[35]
rs80065107
1.39

CXCR5, DDX6
RA, IBD, Celiac

12
12p13
[35]
rs1800693
1.27

TNFRSF1A, LTBR
MS

12q24
[35]
rs11065979
1.20

SH2B3
RA, T1DM, Hyperthyroidism, Celiac

12q24
[34]
rs7309325
1.26

SH2B3
RA, T1DM, Hyperthyroidism, Celiac

13
13q14
[34, 35]
rs3862738
1.33

TNFSF11
CD

14
14q24
[35]
rs911263
1.26

RAD51B
RA

14q32
[32]
rs8017161
1.22

TNFAIP2

16
16p13
[35]
rs12708715
1.29

CLEC16A, SOCS1
MS, UC, T1DM

16q24
[32]
rs11117432
1.31

IRF8
MS, IBD, RA, SSc

17
17q12
[35]
rs17564829
1.26

IKZF3
UC, CD, RA, T1DM

17q21
[35]
rs17564829
1.25

MAPT

19
19p12
[35]
rs34536443
1.91

TYK2
IBD, RA, SLE, psoriasis, T1DM

19p13
[34]
rs73003205
1.35

KIAA1683

19q13
[31]
rs3745516
1.46

SPIB

22
22q13
[35]
rs2267407
1.29

SYNGR1

CD, Crohn’s disease; UC, ulcerative colitis; T1DM, type 1 diabetes mellitus.

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 β2. Modest 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⁺ T cells. Our body of evidence suggests that there may be 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 TNFα loci in the pre-GWAS 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 Sjögren’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.

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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