Evaluation of the role of MHC class II alleles, haplotypes and selected amino acid sequences in primary sclerosing cholangitis.

BACKGROUND AND AIMS: Genetic susceptibility to primary sclerosing cholangitis is associated with several different HLA haplotypes, though a single "shared" susceptibility allele has yet to be identified. Most recently, attention has focussed on the MICA alleles in close proximity to the HLA class I, B locus. However, although there are strong associations with MICA*008, implicating this or a closely linked allele as major risk factors, this explanation alone does not account for all of the MHC-encoded susceptibility and resistance to PSC. The present study re-examines HLA class II associations in a large single centre series of well-characterised PSC patients. The specific aims of the study were to test existing associations and to develop hypotheses which together may account for all, or the majority, of the MHC-encoded susceptibility in PSC.
METHODS: A total of 148 adult white northern European patients and 134 control subjects were studied. HLA DRB1, DQA1, DQB1 alleles and DRB1*04, DRB1*13 and DRB3 subtypes were determined by standard PCR-genotyping.
RESULTS: The primary associations with the DRB3*0101--DRB1*0301--DQA1*0501--DQB1*0201 and DRB1*1301--DQA1*0103--DQB1*0603 haplotypes were confirmed (O.R. = 2.69, p < 0.0000025 and O.R. = 3.8, p < 0.0005). In addition the strong protective influence of the DRB1*04--DQB1*0302 haplotype was reaffirmed (O.R. = 0.26, p < 0.000025) and a previously unreported negative (i.e. protective) association with the DRB1*0701--DQB1*0303 haplotype was also demonstrated (O.R. = 0.15, p < 0.005). Further analysis suggested that susceptibility/resistance encoded by the second and third susceptibility haplotypes and by the two resistance haplotypes may be determined by specific amino acids at DQbeta-87 and DQbeta-55, respectively.