Sequence-based association analysis of HLA class I and II alleles in Japanese supports conservation of common haplotypes

Abstract

Alleles of HLA-A, B, C, DRB1, DQB1, and DPB1 loci were fully determined in 117 healthy Japanese. A*2402, A*3303, A*1101, A*0201, B*4403, B*5201, Cw*0102, Cw*1403, Cw*0304, Cw*0702, Cw*0801, and Cw*1202 showed frequencies of over 10%. Multi-locus haplotype frequencies were estimated by the maximum likelihood method. Strength of association between C and B loci was comparable with that between DRB1 and DQB1 loci. Alleles unidentified by a serological method and having very similar nucleotide sequences (A2: A*0201, A*0206, A*0207, B61: B*4002, B*4006) were carried by different haplotypes. Several frequent five-locus haplotypes were identified including A*3303-Cw*1403-B*4403-DRB1(*)1302-DQB1(*)0604, and A*2402-Cw*1202-B*5201-DRB1(*)1502-DQB1(*)0601. These sequence-based haplotypes corresponded to serology-based common haplotypes which have already been described in Japanese. These findings indicate that common HLA haplotypes consist of particular sets of HLA alleles and that these haplotypes have been conserved through recent human evolution.

Association of HLA-DRB1*0901-DQB1*0303 haplotype with microscopic polyangiitis in Japanese

“…HLA-DQB1*0303 demonstrated statistically significant association as strong as HLA-DRB1*0901. HLA-DQB1*0303 and DRB1*0901 have been shown to be in strong LD, 15,16 which was confirmed in our control subjects (D 0 ¼ 0.95, r 2 ¼ 0.82). A tendency of increase was also observed for HLA-DPB1*0201, B*15111 and Cw*0303.…”

“…Interestingly, one patient was positive for B*15111 in the absence of DRB1*0901 (Table 2C, group c). On the other hand, other HLA-B alleles in LD with DRB1*0901 such as B*4002 and B*4006 15,16 were not increased in MPA (allele carrier frequencies of B*4002: 14.0% in MPA, 10.4% in controls, B*4006: 10.0% in MPA, 11.7% in controls). These results could possibly suggest that B*15111 itself or another gene in linkage disequilibrium with it might have a contribution independent of DRB1*0901.…”

“…As the latter alleles have been also shown to be in LD with HLA-DRB1*0901 in Japanese, 15,16 two-locus analysis was performed between each allele and HLA-DRB1*0901, to distinguish the alleles directly associated with MPA and those that reflect LD with such alleles.…”

Complex divergence at a microsatellite marker C1_2_5 in the lineage of HLA-Cw/-B haplotype

“…In general, human genetic geography showed high continuity, and it is well known that the MHC haplotypes in neighboring populations were introduced to Japan through multiple routes. 28 Therefore, the MHC haplotype structures in the Japanese population might be shaped by multiple immigrations.…”

Association of HLA-A*3303-B*4403-DRB1*1302 haplotype, but not of TNFA promoter and NKp30 polymorphism, with postherpetic neuralgia (PHN) in the Japanese population

“…It is known that strong linkage disequilibria are observed among loci in the HLA region, 11 and a large number of genes that play important roles in the immune response such as tumor necrosis factor a (TNFA) and NKp30 as well as HLA genes are located in this region. Several polymorphisms in the promoter region of TNFA have been reported to influence the expression level of TNFA and to be associated with various human diseases including infectious diseases.…”