HLA class II haplotypes in primary sclerosing cholangitis patients from five European populations
ABSTRACT 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).
- SourceAvailable from: Tobias J Weismüller
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- "PSC as genetic disease – Increased prevalence of PSC among first-degree relatives  – Association with HLA-haplotypes is only weak and not mandatory – Association with certain MHC-and non-MHC-alleles          – Studies on non-HLA polymorphisms are not reproducible or contradictory PSC as an autoimmune disease – Increased incidence of co-existing autoimmune diseases  – No response on immunosuppressive treatment – Presence of multiple autoantibodies  – 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     – 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  – No evidence of sign. bacteraemia in UC  – Helicobacter species can be found in 24–75% of PSC livers   – No evidence of small intestinal bacterial overgrowth or disturbed intestinal permeability in PSC patients  – Helicobacter species are not found more often in livers of PSC patients than in non-cholestatic liver diseases  PSC as a cholangiopathy – Knockout of the Mdr2 gene which encodes a canalicular phospholipid transporter in mice, results in a sclerosing cholangitis   – In human PSC patients a significant variation of the corresponding MDR3-gene could not be found  – Sera of PSC patients contain autoantibodies against a shared peptide in biliary and colon epithelium  – Biliary epithelial cells that are activated by serum-autoantibodies produce cytokines and trigger inflammation   S40 T.J. Weismü ller et al. / Journal of Hepatology 48 (2008) S38–S57 involved in pathogenesis. "
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.Journal of Hepatology 02/2008; 48 Suppl 1(1):S38-57. DOI:10.1016/j.jhep.2008.01.020 · 10.40 Impact Factor
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- "When secondary HLA associations were sought by eliminating all of the patients and controls positive for the primary associated allele or alleles and reanalysing the data, increased HLA-DR2 (DRB1*1501 allele) frequency was observed in PSC patients  . HLA-DR4 has been found to negatively associate with PSC    , suggesting a protective effect of this allele, but, on the contrary, rapid disease progression has been observed in a study in HLA-DR4 positive PSC patients . Thus far any significant associations between PBC and HLA-A or HLA-B antigens have not been found. "
ABSTRACT: A genetic predisposition has been suggested in primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). The aim of the study was to evaluate human leukocyte antigen (HLA) frequencies and HLA associations in Finnish PSC and PBC patients. The relative frequencies of HLA-A,-B, and-DR antigens were compared between patients with PSC (n=50), or PBC (n=89), transplanted due to end-stage liver disease, and healthy members in the Finnish bone marrow donor registry (n=10000). Prevalence differences, prevalence ratios and the associated large-sample significance probabilities (2-sided P-values) and 95% confidence intervals were calculated. We found a strong positive association between PSC and HLA-B8 and-DR3, and a weak positive association between HLA-A1 and PSC. HLA-DR3 also had a weak positive association with PBC, and a weak negative association between HLA-DR5 and PBC was found. In conclusion, HLA-B8, and-DR3 are susceptible for progressive liver disease in PSC, and HLA-DR3 may also be susceptible for disease progression in PBC. HLA-DR5 may be protective against severe PBC.Central European Journal of Medicine 02/2007; 2(1):12-25. DOI:10.2478/s11536-007-0009-3 · 0.21 Impact Factor