DNA typing of HLA class II genes; DRB1*0803 increases the susceptibility of Japanese to primary biliary cirrhosis

doi:10.1016/S0168-8278(05)80617-8

Journal of Hepatology

Volume 21, Issue 6, 1994, Pages 1053-1060

https://doi.org/10.1016/S0168-8278(05)80617-8 Get rights and content

The association between human leukocyte antigens and primary biliary cirrhosis is controversial, but major histocompatibility complex class II antigen DR8 was recently reported to be associated with increased susceptibility for primary biliary cirrhosis in some Caucasians and Japanese. Accordingly, we performed DNA typing of HLA class II genes in Japanese patients with primary biliary cirrhosis. The genotypes of HLA DRB1, DRB3–5, DQA and DQB were determined by polymerase chain reaction and subsequent hybridization with sequence specific oligoncleotides in 31 primary biliary cirrhosis patients and 215 racially matched local controls. DR8 was found in 24 of the 31 primary biliary cirrhosis patients and was highly concentrated in DRB1*0803. The gene frequency of DRB1*0803 was significantly increased in the patients (35.5% vs 7.4%, relative risk=6.84, p<0.0001). DQA1*0103 and DQB1*0601 were also increased in the primary biliary cirrhosis patients, in relation to linkage disequilibrium with DRB1*0803 on the same haplotype. In contrast, DQA1*0102 showed a significantly lower frequency in the primary biliary cirrhosis patients (p<0.05). These data suggest that DRB1*0803 is one of the HLA class II genes related to an increased risk of primary biliary cirrhosis in Japanese individuals.

References (37)

GershwinME et al.
Primary biliary cirrhosis: paradigm or paradox for autoimmunity
Gastroenterology
(1991)
MannsMP et al.
HLA DRw8 and complement C4 deficiency as risk factors in primary biliary cirrhosis
Gastroenterology
(1991)
MaedaT et al.
The association of primary biliary cirrhosis with HLA DRw8 in Japan
International Hepatology Communications
(1993)
TermijtelenA et al.
Oligonucleotide typing is a perfect tool to identify antigens stimulatory in the mixed lymphocyte culture
Hum Immunol
(1991)
BuusS et al.
Isolation and characterization of antigen-Ia complexes involved in T cell recognition
Cell
(1986)
WraithDC et al.
Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy
Cell
(1989)
MocbiusU et al.
T cell receptor gene rearrangements of T lymphocytes infiltrating the liver in chronic active hepatitis B and primary biliary cirrhosis (PBC): oligoclonality of PBC-derived T cell clones
Eur J Immunol
(1990)
SaitohT et al.
Depletion of CD8 cells exacerbates organ-specific autoimmune diseases induced by CD4 T cells i semi-allogenic host with MHC class II disparity
J Immunol
(1990)
StemerwiczR et al.
Are antimitochondrial antibodies in primary biliary cirrhosis induced by r(rough)-mutants of enterobacteriaceae?
Lancet
(1988)
MiyamoriH et al.
HLA antigens in Japanese patients with primary biliary cirrhosis and autoimmune chronic active hepatitis
Digestion
(1983)

ErcillaG et al.

Primary biliary cirrhosis associated with HLA DR3

Tissue Antigens

(1979)

BassendineMF et al.

HLA DR antigens in primary biliary cirrhosis: lack association

Gut

(1985)

JohnstonDE et al.

Histocompatibility antigens in primary biliary cirrhosis

Am J Gastroenterol

(1987)

FuggerL et al.

RFLP of two HLA B associated transcripts genes in five autoimmune diseases

Hum Immunol

(1991)

BriggsDC et al.

A major histocompatibility complex class III allotype, C4B2, associated with primary biliary cirrhosis

Tissue Antigens

(1987)

FuggerL et al.

Nco 1 RFLP of tumor necrosis factor alpha region in primary biliary cirrhosis and in healthy Danes

Scand J Immunol

(1989)

GoresG et al.

Primary biliary cirrhosis: association with class II major histocompatibility complex antigens

Hepatology

(1987)

GregoryWL et al.

Primary biliary cirrhosis: contribution of HLA class II allele DR8

QJ Med

(1993)

Cited by (106)

MicroRNAs in autoimmune liver diseases: from diagnosis to potential therapeutic targets
2020, Biomedicine and Pharmacotherapy
Autoimmune liver diseases (AILDs) are a group of liver disorders composed of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) characterized by chronic hepatic and biliary inflammation. Although several genetic factors, such as HLA alleles, TNFA, and CTLA-4, have been reported in the pathogenesis of AILDs, many details remain unknown. In recent years, microRNAs (miRNAs) have emerged as crucial components in the diagnosis and therapeutic applications of various autoimmune diseases, including systemic lupus erythematosus (SLE), glomerulonephritis, and AILDs. MiRNAs comprise a class of small, noncoding molecules of 19-–25 nucleotides that modulate multiple genes by suppressing or degrading target mRNAs. Altered miRNA profiles have been identified in serum, immune cells, and live tissues from AILD patients. Elevated serum miR-21 and miR-122 levels in AIH patients as well as decreased miR-200c levels in PSC patients indicate their diagnostic utility. Highly expressed miR-122 and miR-378f as well as downregulated miR-4311 and miR-4714-3p in serum samples from refractory PBC patients suggest their potential to evaluate treatment efficacy. Moreover, miRNAs have been reported to participate in AILD development. Increased miR-506 levels may impair bile secretion in PBC by inhibiting Cl-/HCO3-anion exchanger 2 (AE2) and type III inositol 1,4,5-trisphosphate receptor-3 (InsP3R3). Additionally, different miRNA mimics or antagonists, such as atagomiR-155 and miR-223 mimics, have been widely applied in experimental AILD murine models with great efficacy. Here, we provide an overview of miRNAs in AILDs, aiming to summarize their potential roles in diagnosis and therapeutic interventions, and we discuss the challenges and future applications of miRNAs in clinical practice.
Primary biliary cholangitis
2019, The Autoimmune Diseases
Primary biliary cholangitis (PBC), formally known as primary biliary cirrhosis, is a chronic cholestatic liver disease that mainly affects middle-aged women. PBC, if untreated, can progress to liver failure and death; liver transplantation is the only curative therapeutic option. Ursodeoxycholic acid (UDCA) has been proven to improve the long-term prognosis of patients with PBC and is approved as the first-line treatment for PBC in clinical practice, while almost 30% of the patients are refractory to UDCA treatment and can progress to cirrhosis in the absence of appropriate second-line treatment. Recently obeticholic acid (OCA), a farnesoid X receptor agonist, was approved for UDCA-refractory or UDCA-intolerant patients. However, the efficacy of OCA is still suboptimal and more new therapeutic approaches are seriously awaited. In this regard, we need to know more about the etiology of PBC, to identify more appropriate and specific biomarkers that predict the clinical course and also to know which therapies are applicable at different stages, since treatment for PBC should be individualized based on stratification of the risk for progression.
The Genetics and Epigenetics of Primary Biliary Cholangitis
2018, Clinics in Liver Disease
Citation Excerpt :
In case-control studies, because encompassing whole genome like in GWAS is impossible and targeted area for searching needs to be limited, HLA alleles have been of particular interest and extensively studied. HLA class II alleles were found to be associated with the development of PBC, especially DRB1*08 allele family, that is, DRB1*0801, DRB1*0803, DRB1*14, and DPB1*0301 as susceptible and DRB1*11, DRB1*13 as protective alleles; as expected, these associations vary depending on populations studied.22–25 Although HLA alleles are definitely crucial in determining the susceptibility of PBC via the alteration of autoantigen presentation, the involvement of HLA alleles in PBC susceptibility is complex; some are susceptible, whereas others are protective, and how HLA alleles influence the susceptibility is largely not clear.
Primary biliary cirrhosis
2015, The Lancet
Primary biliary cirrhosis is a chronic cholestatic liver disease characterised by destruction of small intrahepatic bile ducts, leading to fibrosis and potential cirrhosis through resulting complications. The serological hallmark of primary biliary cirrhosis is the antimitochondrial antibody, a highly disease-specific antibody identified in about 95% of patients with primary biliary cirrhosis. These patients usually have fatigue and pruritus, both of which occur independently of disease severity. The typical course of primary biliary cirrhosis has changed substantially with the introduöction of ursodeoxycholic acid (UDCA). Several randomised placebo-controlled studies have shown that UDCA improves transplant-free survival in primary biliary cirrhosis. However, about 40% of patients do not have a biochemical response to UDCA and would benefit from new therapies. Liver transplantation is a life-saving surgery with excellent outcomes for those with decompensated cirrhosis. Meanwhile, research on nuclear receptor hormones has led to the development of exciting new potential treatments. This Seminar will review the current understanding of the epidemiology, pathogenesis, and natural history of primary biliary cirrhosis, discuss management of the disease and its sequelae, and introduce research on new therapeutic options.
Role of genetics in diagnosis and therapy of acquired liver disease
2014, Molecular Aspects of Medicine
Citation Excerpt :
As with other autoimmune disease, HLA associations in PBC do not come as a surprise, and there are many previous smaller scale candidate gene studies underscoring the relevance of the HLA system for PBC pathogenesis. For example, strong associations have been described in the HLA class II DRB1*08 region, especially DRB1*0801 in European and Japanese patients (Donaldson et al., 2006; Mullarkey et al., 2005; Onishi et al., 1994). However, the role of aberrant immunoregulatory IL-12 signalling axis for PBC development as suggested by the GWAS, second only to the HLA associations, has attracted widespread attention.
By implementation of novel genotyping technologies, progress in delineating the genetic architecture of acquired liver diseases has been achieved in recent years. The rapid dissemination of genome-wide linkage and association studies has paved the way for the identification of genetic variants that cause or modify non-viral liver diseases as well as the natural and treatment-related outcomes in chronic viral hepatitis. Invaluable genomic data has recently been derived from additional genome-wide association studies (GWAS) of the archetypical cholestatic liver diseases primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Beyond providing novel pathobiological insights in need of more sophisticated functional annotation, gene variation might in the future be instrumental in precise risk stratification and the development of genotype-based treatment algorithms. In this regard, the definition of subtypes of acquired liver disease and re-categorization of clinically defined disease phenotypes into a more ‘genometype’-based disease classification represents a priority future research direction.
HLA-DR Polymorphism and Primary Biliary Cirrhosis: Evidence From a Meta-analysis
2014, Archives of Medical Research
Citation Excerpt :
In view of the low resolution of RFLP-PCR method, the studies (20,24,95–97) using RFLP-PCR method were also excluded from this study. Finally, this meta-analysis, which included a total number of 6057 cases and 16107 controls, identified 19 articles (or 20 studies including the substudies) on HLA-DR polymorphisms (11,12,21-23,25,83,98–109) (Figure 1). The most commonly investigated polymorphisms were HLA-DR1, DR3, DR4, DR8, DR11, DR13, DR15, which were reported in 14, 10, 14, 19, 16, 17 and 14 studies, respectively.
We undertook this study to review and quantitatively analyze the association between human leukocyte antigen (HLA) DR polymorphisms and susceptibility of primary biliary cirrhosis (PBC).
All relevant publications on the association between HLA-DR polymorphisms and PBC were searched through June 2013. Odds ratios (OR) and confidence intervals (CI) for the comparisons between case and control group were calculated. Statistical analysis was performed using Stata 11.0 software.
Nineteen articles (or 20 studies including the substudies) were identified. For DR*7 allele, the ORs (95% CIs) were 1.530 (1.310, 1.788), 1.757 (1.285, 2.403) and 1.495 (1.211, 1.845) in overall, Asian and European populations, respectively. For DR*8 alleles, the ORs (95% CIs) were 3.158 (1.822, 5.475), 2.803 (2.420, 3.247) and 3.056 (2.573, 3.629) in Asian, American and European subgroups, respectively. The subgroup analysis for DR*11 and DR*13 showed a significant association in Asian and European population. For DR*12 and *15 alleles, the overall ORs (95% CIs) were 0.551 (0.404, 0.753) and 0.721 (0.607, 0.857). However, in subgroup analysis for DR*12 allele, the association was only found in Asian population. In addition, statistical significance exists in American and European populations in the subgroup analysis for DR*15 allele.
Our meta-analysis suggested that HLA-DR *7 and *8 allele polymorphisms contributed to the susceptibility of PBC, whereas DR*11, *12, *13 and *15 allele polymorphisms are protective factors in certain population.

View all citing articles on Scopus

View full text

Regular PaperDNA typing of HLA class II genes; DRB1*0803 increases the susceptibility of Japanese to primary biliary cirrhosis

Gastroenterology

Gastroenterology

International Hepatology Communications

Hum Immunol

Cell

Cell

T cell receptor gene rearrangements of T lymphocytes infiltrating the liver in chronic active hepatitis B and primary biliary cirrhosis (PBC): oligoclonality of PBC-derived T cell clones

Eur J Immunol

Depletion of CD8 cells exacerbates organ-specific autoimmune diseases induced by CD4 T cells i semi-allogenic host with MHC class II disparity

J Immunol

Are antimitochondrial antibodies in primary biliary cirrhosis induced by r(rough)-mutants of enterobacteriaceae?

Lancet

HLA antigens in Japanese patients with primary biliary cirrhosis and autoimmune chronic active hepatitis

Digestion

Primary biliary cirrhosis associated with HLA DR3

Tissue Antigens

HLA DR antigens in primary biliary cirrhosis: lack association

Gut

Histocompatibility antigens in primary biliary cirrhosis

Am J Gastroenterol

RFLP of two HLA B associated transcripts genes in five autoimmune diseases

Hum Immunol

A major histocompatibility complex class III allotype, C4B2, associated with primary biliary cirrhosis

Tissue Antigens

Nco 1 RFLP of tumor necrosis factor alpha region in primary biliary cirrhosis and in healthy Danes

Scand J Immunol

Primary biliary cirrhosis: association with class II major histocompatibility complex antigens

Hepatology

Primary biliary cirrhosis: contribution of HLA class II allele DR8

QJ Med

Regular Paper
DNA typing of HLA class II genes; DRB1*0803 increases the susceptibility of Japanese to primary biliary cirrhosis