In this study, we investigated the five polymorphic Alu loci located within human major histocompatibility complex (MHC) class I region in 445 individuals from four distinct Chinese populations: Hunan Han, Inner Mongolia Han, Inner Mongolia Mongol and Guangdong Han populations, with an emphasis on the linkage disequilibrium (LD) between Alu insertions and human leukocyte antigen (HLA)-A, Cw and B loci in a southern (Hunan Province) and a northern (Inner Mongolia Autonomous Region) Chinese Han population. Our data showed that (a) the allele and haplotype frequencies of Alu and HLA-A loci did not differ significantly between the two southern Chinese Han populations and showed remarkable homogeneity in the two northern Chinese populations; (b) AluyHG had the highest insertion rate and HLA-A*02 harboring the single AluyHG insertion was most frequent among Alu insertion-bearing haplotypes in all four populations; (c) haplotypes AluyHF insertion-HLA-A*26, AluyHG insertion-HLA-A*02 and AluyHJ insertion-HLA-A*24 were in significant LD across the four groups and (d) haplotype AluyMICB insertion-HLA-Cw*06 was in significant LD in both populations, while significant LD of haplotypes AluyMICB insertion-HLA-B*54 and AluyMICB insertion-HLA-B*48 was only observed in the Hunan Han population and the Inner Mongolia Han population, respectively. Haplotype HLA-B*48-MICA gene deletion-AluyMICB insertion was observed at a frequency of about 3.85% in the latter population. Our data, together with previous reports on several Asian-Oceanian populations suggest the identity by descent of several common HLA-A allelic lineages in these modern human populations. The novel population-specific LD patterns uncovered in this study also shed new insight into HLA evolution and haplotype origin.

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In this study, we typed 930 cases of nasopharyngeal carcinoma (NPC) and 1134 normal controls recruited from Hunan province, southern China for human leukocyte antigen-A (HLA-A) locus by sequencing exons 2-4. Very significant associations between HLA-A*02:07, HLA-A*11:01 and NPC were established [25.7% vs 16.18%; odds ratio, OR (95% confidence interval, CI) = 1.79 (1.54-2.09), P < 0.0001 and 21.1% vs 30.42%, OR (95% CI) = 0.61 (0.53-0.70), P<0.0001, respectively]. Further analysis of the molecular basis underlying these associations suggests that cysteine (C) at codon 99 of α2-helix of HLA-A protein is probably deleterious and confers risk to NPC. Convincing evidence was uncovered for negative association of a rare allele in southern Chinese populations, HLA-A*31:01, with NPC [0.22% vs 2.12%, OR (95% CI) = 0.1 (0.04-0.28), P < 0.0001]. rs1059449-A, which encodes arginine (R) at codon 56 of α1-helix of HLA-A protein, was postulated to be crucial for such a pattern of negative association with NPC. A subset of NPC cases (N = 632) and normal controls (N=712) were tested for anti-virus capsid antigen (anti-VCA) immunoglobulin A (IgA), very significant difference in seropositivity for anti-VCA IgA was observed between the two groups [67.56% vs 6.46%, OR (95% CI) = 30.16 (21.42-42.46), P < 0.0001]. However, seropositivity for anti-VCA IgA did not correlate with HLA-A allelic typing in both groups.

Deletion of major histocompatibility complex class I chain-related genes A (MICA*Del) was investigated in 3,411 DNA samples from two southern Chinese Han populations (Hunan Han, HNH; Guangdong Han, GDH), two northern Chinese populations (Inner Mongolia Han, IMH; Inner Mongolia Mongol, IMM) and one southeastern Chinese Han population (Fujian Han, FJH) using an in-house polymerase chain reaction-sequence specific priming (PCR-SSP) assay, which enables direct discrimination between heterozygote and homozygote for MICA*Del. MICA*Del showed a frequency ranging from 0.8% in FJH to 5.7% in IMM (P < 0.05), indicating northward increase in frequency of MICA*Del in Chinese populations. In contrast to the association reported recently in a Taiwan Chinese population and a Malaysian Chinese cohort, MICA*Del distribution did not differ between 1,120 patients with nasopharyngeal carcinoma (NPC) and 1,483 normal controls in the HNH population (1.03% in NPC cases vs 1.18% in the controls, OR (95% CI) = 0.87 (0.51-1.47), p = 0.69). Further gender-stratified analysis also failed to disclose any male-specific association reported in a Taiwan Chinese population. Multi-locus typing of the 94 samples carrying MICA*Del revealed two new haplotypes, HLA-A*11:01-B*13:01-MICA*Del-MICB*009N-DRB1*04:06 and HLA-B*35:01-MICA*Del-MICB*009N-DRB1*15:01, in addition to HLA-B*48-MICA*Del. Unexpectedly, two samples with MICA*Del in the HNH population were each consistently found to have two distinct MICA alleles, indicating the existence of two MICA gene copies on certain HLA haplotypes. Based on the results from a sizeable case-control study, our data suggest that there is no association between MICA*Del and NPC in the southern Chinese Han population.