HLA class II haplotypes in primary sclerosing cholangitis patients from five European populations

University of Oslo, Kristiania (historical), Oslo, Norway
Tissue Antigens (Impact Factor: 2.14). 05/1999; 53(5):459-69. DOI: 10.1034/j.1399-0039.1999.530502.x
Source: PubMed


The association of primary sclerosing cholangitis (PSC) to HLA class II genes was studied by comparing patients from five different European populations. Deduced HLA-DRB1, DQA1, DQB1 haplotypes of 256 PSC patients from England, Italy, Norway, Spain and Sweden were compared to those observed in 764 ethnically-matched controls. Increased frequencies of the DRB1*03, DQA1*0501, DQB1*02 (RR=3.0, P<0.00001) and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes (RR=2.4, P<0.0001) were observed in all five patient groups. A total of 16% of the PSC patients were homozygous for the DRB1*03, DQA1*0501, DQB1*02 haplotype compared to 1% of the controls (RR=20, P<0.0001). The DRB1*04, DQA1*03, DQB1*0302 haplotype was significantly reduced in frequency(RR=0.4, P<0.00001). Among Norwegian, Swedish and British patients that did not carry neither the DRB1*03, DQA1*0501, DQB1*02 nor the DRB1*13, DQA1*0103, DQB1*0603 haplotype, an increased frequency of the DRB1*15, DQA1*0102, DQB1*0602 haplotype was observed (RR=2.0, P<0.0001). Thus, PSC was found to be positively associated to three different HLA class II haplotypes (i.e. the DRB1*03, DQA1*0501, DQB1*02, the DRB1*15, DQA1*0102, DQB1*0602 and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes) and negatively associated to one HLA class II haplotype (i.e. the DRB1*04, DQB1*0302 haplotype).

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    • "The highest relative risk to develop PSC is conferred by the DRB1*03, DQA1*0501, DQB1*02 homozygous genotype [21]. Approximately half of all PSC patients in Norway and Sweden carry at least one of these haplotypes [23], whereas none of these haplotype associations was detected in PSC patients from Italy and only the DRB1*13, DQA1*0103, DQB1*0603 was present in PSC patients from Brazil [14,15,21,23]. These data underscore the considerable heterogeneity in both HLA classes of different populations and may contribute to the observed differences. "
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    ABSTRACT: Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease with fibroobliterative sclerosis of intra- and/or extrahepatic bile ducts, eventually leading to biliary cirrhosis. The association with human leukocyte antigen (HLA) and non-HLA haplotypes and the presence of autoantibodies in sera of PSC patients support a crucial role for immune-mediated mechanisms in the initiation and progression of PSC. The strong clinical association between PSC and inflammatory bowel diseases led to intriguing pathogenetic concepts, in which the inflamed gut with translocation of bacterial products and homing of gut-primed memory T lymphocytes via aberrantly expressed adhesion molecules plays a fundamental role. Genetically or chemically modified bile composition was shown to induce sclerosing cholangitis and liver fibrosis in a number of animal models ("toxic bile concept"). The potential role of vascular injury with ischemia of bile duct epithelium cells in the development of sclerosing cholangitis is supported by animal models of endothelial cell injury showing close morphological similarities with human PSC.
    Full-text · Article · Dec 2011 · Best practice & research. Clinical gastroenterology
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    • "Both environmental and genetic risk factors have been associated with PSC susceptibility, in some cases being common to the IBD background, as in the case of smoking [5-7]. Interestingly, the association of PSC with the human leukocyte antigen DR3-B8-A1 haplotype found in Northern European populations [8,9] has not been reproduced in Italian or Brazilian PSC cohorts suggesting that genetic risks for PSC may vary between populations [10,11]. In African-Americans patients listed for liver transplantation in the US, we have recently shown that PSC is associated with HLA-B8, but not HLA-DR3 suggesting a common genetic risk factor near the HLA-B locus [12]. "
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    ABSTRACT: Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease often associated with inflammatory bowel diseases (IBD). Current epidemiological data are limited to studies of predominantly Caucasian populations. Our aim was to define the epidemiology of PSC in a large, ethnically diverse US population. The Northern California Kaiser Permanente (KP) database includes records from over 3 million people and was searched for cases of PSC between January 2000 and October 2006. All identified charts were reviewed for diagnosis confirmation, IBD co-morbidity, and major natural history endpoints. We identified 169 (101 males) cases fulfilling PSC diagnostic criteria with a mean age at diagnosis of 44 years (range 11-81). The age-adjusted point prevalence was 4.15 per 100,000 on December 31, 2005. The age-adjusted incidence per 100,000 person-years was not significantly greater in men 0.45 (95% CI 0.33-0.61) than women 0.37 (95% CI 0.26-0.51). IBD was present in 109/169 (64.5%) cases and was significantly more frequent in men than women with PSC (73.3% and 51.5%, respectively, p = 0.005). The cumulative average yearly mortality rate was 1.9%. Age and serum sodium, creatinine and bilirubin at diagnosis and albumin at last entry were identified as significant factors associated with death, liver transplant or cholangiocarcinoma. The incidence and prevalence of PSC observed in a representative Northern California population are lower compared to previous studies in Caucasian populations and this might reflect differences in the incidence of PSC among various ethnic groups.
    Full-text · Article · Jul 2011 · BMC Gastroenterology
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    • "PSC as genetic disease – Increased prevalence of PSC among first-degree relatives [21] – Association with HLA-haplotypes is only weak and not mandatory – Association with certain MHC-and non-MHC-alleles [23] [24] [25] [26] [27] [28] [29] [30] [31] – Studies on non-HLA polymorphisms are not reproducible or contradictory PSC as an autoimmune disease – Increased incidence of co-existing autoimmune diseases [20] – No response on immunosuppressive treatment – Presence of multiple autoantibodies [33] – Male predominance – Antibodies are not specific and do not correlate with clinical parameters PSC as inflammatory reaction on infectious agents – Co-expression of VAP-1 and MadCAM-1 in the gut and the liver of patients with PSC and IBD allows an enterohepatic lymphocyte circulation [41] [42] [44] [45] – In PSC patients without IBD enterohepatic lymphocyte circulation is not a conclusive concept – In a rat model small intestinal bacterial overgrowth lead to biliary strictures and portal inflammation [48] – No evidence of sign. bacteraemia in UC [46] – Helicobacter species can be found in 24–75% of PSC livers [50] [52] – No evidence of small intestinal bacterial overgrowth or disturbed intestinal permeability in PSC patients [49] – Helicobacter species are not found more often in livers of PSC patients than in non-cholestatic liver diseases [51] PSC as a cholangiopathy – Knockout of the Mdr2 gene which encodes a canalicular phospholipid transporter in mice, results in a sclerosing cholangitis [61] [62] – In human PSC patients a significant variation of the corresponding MDR3-gene could not be found [63] – Sera of PSC patients contain autoantibodies against a shared peptide in biliary and colon epithelium [65] – Biliary epithelial cells that are activated by serum-autoantibodies produce cytokines and trigger inflammation [66] [67] S40 T.J. Weismü ller et al. / Journal of Hepatology 48 (2008) S38–S57 involved in pathogenesis. "
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    ABSTRACT: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, characterized by progressive inflammation and fibrosis of the bile ducts, resulting in biliary cirrhosis and is associated with a high risk of cholangiocarcinoma. The majority of patients are young, male and have coexisting inflammatory bowel disease. PSC is found with a prevalence of 10/100,000 in Northern European populations. The pathophysiology of PSC is a complex multistep process including immunological mechanisms, immunogenetic susceptibility and disorders of the biliary epithelia. The diagnosis is primarily based on endoscopic cholangiography although magnetic resonance imaging is increasingly used; biochemistry and immunoserology as well as histology play only a minor role. Due to the high risk of developing cholangiocarcinoma and also other tumours of the GI tract, surveillance strategies are essential, however they have yet to be established and evaluated. Biochemical parameters, clinical risk factors, endoscopic procedures and imaging techniques contribute to the early identification of patients at risk. Since medical therapy of PSC with ursodeoxycholic acid does not improve survival, to date, liver transplantation is the only option with a cure potential; if transplantation is accurately timed, transplanted PSC patients have an excellent rate of survival. However if cholangiocarcinoma is detected, a curative treatment is not possible in the majority of cases. The present review critically summarizes the current knowledge on the aetiopathogenesis of PSC and gives an overview of the diagnostic approaches, surveillance strategies and therapeutic options. Primary sclerosing cholangitis is a disease of unknown aetiology and without any further curative treatment options apart from liver transplantation. Therefore it may be regarded as the greatest challenge in hepatology today.
    Full-text · Article · Feb 2008 · Journal of Hepatology
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