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Identification of the primary allele(s) in  HLA class II  associated diseases remains challenging because of a tight linkage between alleles of  HLA-DR  and  -DQ  loci. In the present study, we determined the genotypes of seven  HLA  loci ( HLA-A ,  -B ,  -DRB1 ,  -DQA1 ,  -DQB1 ,  -DPA1  and  -DPB1 ) for 1200 Japanese patients with primary biliary cholangitis and 1196 controls. Observation of recombination derivatives facilitated an evaluation of the effects of individual  HLA  alleles consisting of disease-prone/disease-resistant  HLA  haplotypes. Consequently, a primary contribution of  DQB1*06:04  (odds ratio: 0.19, p = 1.91 × 10 −22 ),  DQB1*03:01  (odds ratio: 0.50, p = 6.76 × 10 −10 ),  DRB1*08:03  (odds ratio: 1.75, p = 1.01 × 10 −7 ) and  DQB1*04:01  (odds ratio: 1.50, p = 9.20 × 10 −6 ) was suggested. Epistasis of the protective  DQB1*06:04  to risk conferred by  DRB1*08:03  was demonstrated by subpopulation analysis, implicating the presence of an active immunological mechanism that alleviates pathogenic autoimmune reactions. Further, the contribution of the aforementioned  HLA  alleles as well as an  HLA-DP  allele,  DPB1*02:01  to the association signals of 304 loci among 4103 SNPs in the  HLA  region at the genome-wide level of significance (p values less than 5 × 10 −8 ) was demonstrated by the stepwise exclusion of the individuals possessing these  HLA  alleles from the comparison.

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Principal contribution of HLA-DQ alleles, DQB1*06:04 and DQB1*03:01, to disease resistance against primary biliary cholangitis in a Japanese population