Evaluation of the role of MHC class II alleles, haplotypes and selected amino acid sequences in primary sclerosing cholangitis.
OBJECTIVE
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.
Donaldson
Peter T
PT
Centre for Liver Research, School of Clinical Medical Sciences, Faculty of Medical Science, University of Newcastle, Newcastle upon Tyne, NE2 4HH, UK. p.t.donaldson@ncl.ac.uk
Norris
Suzanne
S
D020816:Amino Acid Motifs; D015209:Cholangitis, Sclerosing / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics / Q000378:metabolism; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000378:metabolism; D059811:HLA-DRB1 Chains; D059826:HLA-DRB3 Chains; D059845:HLA-DRB4 Chains; D006239:Haplotypes; D006801:Humans; D008297:Male
D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; D059826:HLA-DRB3 Chains; D059845:HLA-DRB4 Chains