Article

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

Institute of Immunology, National Hospital, Oslo, Norway.
Tissue Antigens (Impact Factor: 2.35). 05/1999; 53(5):459-69. DOI: 10.1034/j.1399-0039.1999.530502.x
Source: PubMed

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).

0 Bookmarks
 · 
72 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autoimmune diseases affecting the liver are mainly represented by autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The characteristic morphologic patterns of injury are a chronic hepatitis pattern of damage in AIH, destruction of small intrahepatic bile ducts in PBC and periductal fibrosis and inflammation involving larger bile ducts in PSC. The factors responsible for initiation and perpetuation of the injury in all the three autoimmune liver diseases are not understood completely but are likely to be environmental triggers on the background of genetic variation in immune regulation. In this review, we summarise the current understanding of the mechanisms underlying the breakdown of self-tolerance in autoimmune liver diseases.
    Seminars in Immunopathology 08/2014; 36(5). DOI:10.1007/s00281-014-0439-3 · 6.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Primary sclerosing cholangitis (PCS) is a cholestatic liver disease characterized by chronic destruction and stricturing of the biliary tree, leading to fibrosis and liver cirrhosis. The underlying mechanisms of the disease are poorly understood. Areas covered: Multiple agents with various pharmacological activities have been examined in PSC patients with disappointing results. Ursodeoxycholic acid (UDCA) is by far the most extensively studied agent in PSC. Large prospective trials have failed to demonstrate a positive long-term effect of UDCA in patients with PSC. Antimicrobials have been examined in PSC patients but long-term outcome data are lacking. Immunosuppressive agents were tested in patients with PSC but the majority of these agents were associated with adverse side effects. Nor-UDCA is a newly emerging C23 homolog of UDCA that has shown promising results in experimental studies. The farnesoid X receptor agonists are an attractive class of drugs and are currently being studied in patients with primary biliary cirrhosis. Antifibrotic agents have yielded encouraging results in animal models of PSC but are yet to be evaluated in humans. Expert opinion: Currently, there is no effective treatment for PSC. It is our hope that the newly discovered potential therapeutic routes will lead to the discovery of a curative agent for this debilitating disease.
    06/2014; 2(6). DOI:10.1517/21678707.2014.908701
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetic variants within the major histocompatibility complex (MHC) represent the strongest genetic susceptibility factors for primary sclerosing cholangitis (PSC). Identifying the causal variants within this genetic complex represents a major challenge due to strong linkage disequilibrium and an overall high physical density of candidate variants. We aimed to refine the MHC association in a geographically restricted PSC patient panel. A total of 365 PSC cases and 368 healthy controls of Scandinavian ancestry were included in the study. We incorporated data from HLA typing (HLA-A, -B, -C, -DRB3, -DRB1, -DQB1) and single nucleotide polymorphisms across the MHC (n = 18,644; genotyped and imputed) alongside previously suggested PSC risk determinants in the MHC, i.e. amino acid variation of DRβ, a MICA microsatellite polymorphism and HLA-C and HLA-B according to their ligand properties for killer immunoglobulin-like receptors. Breakdowns of the association signal by unconditional and conditional logistic regression analyses demarcated multiple PSC associated MHC haplotypes, and for eight of these classical HLA class I and II alleles represented the strongest association. A novel independent risk locus was detected near NOTCH4 in the HLA class III region, tagged by rs116212904 (odds ratio [95% confidence interval] = 2.32 [1.80, 3.00], P = 1.35×10-11). Our study shows that classical HLA class I and II alleles, predominantly at HLA-B and HLA-DRB1, are the main risk factors for PSC in the MHC. In addition, the present assessments demonstrated for the first time an association near NOTCH4 in the HLA class III region.
    PLoS ONE 12/2014; 9(12):e114486. DOI:10.1371/journal.pone.0114486 · 3.53 Impact Factor