MICAGene Deletion in 3411 DNA Samples from Five Distinct Populations in Mainland China and Lack of Association with Nasopharyngeal Carcinoma (NPC) in a Southern Chinese Han population

Abstract

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.

High-Throughput MICA/B Genotyping of Over Two Million Samples: Workflow and Allele Frequencies

“…This is concordant to previous studies which present allele frequencies between 43 and 55% for MICA * 008, 8-14% for MICA * 002 and 4-8% for MICA * 009 in European/American populations (7)(8)(9). Although MICA * 008 is also the most common allele in China, with a frequency of about 25% it is far less abundant than in European/American populations (10,11,41). Since MICA * 008 and other rare alleles bearing the A5.1 microsatellite marker are more prone to produce sMICA than other alleles, they are more effective in inactivating NKG2D and NK/T cell activity (15).…”

“…However, given the incomplete sequence coverage, our workflow cannot distinguish MICB * 003, MICB * 005, MICB * 006, and MICB * 010. Studies on Asian cohorts report allele frequencies of at least 55% for MICB * 005, 3% for MICB * 003 and no observations of MICB * 006 or MICB * 010 (10,11,13). Limited full gene analysis of 51 samples with MICB * 005# pre-typing results indicated a similar distribution in our dataset (data not shown).…”

“…Frequencies above 5% were observed for MICA * 002, MICA * 009, MICA * 004, MICA * 010, and MICA * 007 in Europeans. In Chinese cohorts, the alleles MICA * 019, MICA * 027, and MICA * 045 are also common (7)(8)(9)(10)(11). The less diverse MICB gene has been predominantly studied in Asian populations.…”

“…There, the allele MICB * 005 is the most common allele with frequencies of over 50%. It is followed by MICB * 002 and MICB * 004 with frequencies over 10% and MICB * 008 and the null allele MICB * 009N with frequencies over 5% (10)(11)(12)(13).…”

A laboratory practice that uses the polymerase chain reaction‐sequence specific priming technique to rapidly screen for HLA‐DR2 allotype from germline DNA in immunology course for undergraduate medical students

“…Although this protocol was designed for working with DNA extracted from fresh human peripheral blood samples, it is highly compatible and reproducible when using DNA template obtained from different sources. We have used PCR‐SSP technology with a combination of primers to assess the distribution and population genetics of other HLA loci such HLA‐E in Chinese ethnic groups; PCR‐SSP has also been applied by us to investigate the copy number variation (CNV) of MICA gene in Chinese ethnic groups and its potential association with nasopharyngeal carcinoma which exhibits the highest incidence rate in populations of southern Chinese ancestry . These data collectively show the accuracy, discriminative capacity, and suitableness of PCR‐SSP for both teaching and research purposes.…”