Gender-specific associations between MICA-STR and nasopharyngeal carcinoma in a southern Chinese Han population

Abstract

Previous studies have identified several HLA-B specificities that are associated with nasopharyngeal carcinoma (NPC) in populations of Chinese descent, in particular HLA-B35, -B38, -B46, and -B58. Perhaps except for HLA-B46, other associations cannot be simply accounted for by the linkage disequilibrium between HLA-A and B loci. The human major histocompatibility complex (MHC) class I chain-related gene A (MICA) maps 46 kb centromeric to HLA-B and is highly polymorphic; it encodes a stress-inducible protein which functions as a ligand for the NKG2D/DAP10 complex to activate natural killer (NK) cells, gammadelta T cells, and CD8(+) T cells. We postulated MICA gene as a susceptibility factor for nasopharyngeal carcinoma, an Epstein-Barr virus-associated malignancy. In this study, 218 unrelated patients newly diagnosed with NPC and 196 randomly selected healthy controls from southern China mainland were analyzed for the short tandem repeat polymorphism of exon 5 of MICA gene (MICA-STR) and MICA gene deletion, using fluorescent polymerase chain reaction-gene scanning (PCR/size-sequencing) and polymerase chain reaction-sequence-specific priming (PCR/SSP) technology. MICA*A9 was present at significantly increased frequency in the patient group (P (C)=0.0001002, OR=2.528, 95% CI=1.636-3.907), whereas the frequency of MICA*A5.1 was significantly decreased (P (C)=0.006, OR=0.594, 95% CI=0.437-0.806). Gender-based stratification revealed a significant increase of MICA*A9 frequency (P (C)=0.000072, OR=3.255, 95% CI=1.855-5.709) and a significant decrease of MICA*A5.1 frequency (P (C)=0.000737, OR=0.486, 95% CI=0.337-0.702) in male patients with NPC (N=166), compared with male normal controls (N=120). A significant interaction between MICA*A9 and gender was observed ([see text]=41.58, P=0.0001). Statistics also revealed heterogeneity of effects among MICA*A5.1/MICA*A9-bearing phenotypes and a dose-dependent effect of MICA*A5.1 and MICA*A9 on NPC risk in male subgroup. This constitutes the first demonstration of a gender-specific association between MICA-STR polymorphism and NPC, which could largely be attributable to the underlying gender-related mechanisms that modulate MICA gene expression. The results provide strong supporting evidence suggesting that MICA*A9 may be a genetic risk factor for NPC in male individuals in this population. The potential interaction between MICA and other non-HLA host factors and environmental exposures remains to be further studied.

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

“…We did not have serum samples from our cases and controls to examine associations with serum levels in childhood ALL. It is still unclear why there may be a sex effect in HLA complex associations, but in light of similar findings in other diseases (Meyer et al 2001;Fisher et al 2002;Hensiek et al 2002;Tian et al 2006), this aspect of the association we are reporting here warrants further study. In two rat models, HSP70 has a higher expression level in males in response to a viral infection (Klein et al 2004) or following acute tail-shock stress (Nickerson et al 2006) in lymphoid organs.…”

High frequencies of alleles MICA*020 and MICA*027 in Amerindians and evidence of positive selection on exon 3

“…The A10 STR allele (Table 2), which is associated exclusively with allele MICA*020, has thus far been found in just a single chromosome in a Hunan Han population of Southern China. 18 The STR_MICA alleles A5 and A9 occurred at high frequencies (420%) in all five Amerindian populations ( Table 2). In addition, A10 and the deletion of the MICA gene were frequent (47%) only in Kaingang, whereas A6 was frequent (9%) only in Guarani Kaiowá.…”

“…The STR allele A10 has been found in a Hunan Han population of Southern China in a single chromosome, along with HLA-B*5801. 18 In the Kaingang population, the allele was found in a different haplotype, MICA*020-HLA-B*3505-HLA-Cw*0401. The Kaingang HLA-B35 alleles were -B*3501, -B*3506 or -B*3505, the latter two being exclusively found in Amerindians from South America and thought to have originated in this continent by gene conversion with HLA-B*3501 as the founding allele.…”

“…In the populations from this study it is MICA*01801. 18 Another frame shift mutation is caused by a G deletion at the 3 0 end of exon 4, in alleles MICA*015 and MICA*017. Consequently, exon 5 encodes a novel polypeptide containing 12 leucine residues, as a result of the (GCT) 9 STR allele, and a premature stop codon is created at the beginning of exon 6.…”

<B>Nasopharyngeal Carcinoma: an Enigmatic Tumor</B>

“…A recent finding has shown that polymorphisms or haplotype in the MMP2 promoter could possibly play a role in mediating susceptibility to NPC in Chinese populations (Zhou et al, 2007). As for the observation that NPC is more common in males than females, a gender association between exon5 of the MICA gene which increases susceptibility to NPC has been observed (Tian et al, 2006).…”