Multiple low-frequency and rareHLA-Ballelic variants are associated with reduced risk in 1,105 nasopharyngeal carcinoma patients in Hunan province, southern China

In our study, 1,105 cases of nasopharyngeal carcinoma (NPC) and 1,430 normal controls recruited from Hunan province, southern China were typed for human leukocyte antigen (HLA)-Blocus by Sanger sequencing exons 2-4. Besides confirming the NPC association withHLA-B*46:01allele,HLA-A*02:07-B*46:01andHLA-A*33:03-B*58:01haplotypes (all positive), andHLA-B*13lineage (negative), all of which were relatively common, strong negative associations were observed for five low-frequency and rare alleles or lineages, includingHLA-B*07,-B*27:04,-B*39,-B*51:02and-B*55:02, with odds ratio (OR) ranging from 0.16 to 0.3 (allp(corrected)< 0.05). These strong protective associations were independent of linkage disequilibrium (LD) betweenHLA-AandHLA-Bloci. Further analysis indicated a single amino acid change from histidine to tyrosine at residue 171 is probably crucial for the mutant allele,HLA-B*51:02, to mediate resistance to NPC. A subset of NPC cases (n= 821) and normal controls (n= 1,035) were tested for antivirus capsid antigen immunoglobulin A (anti-VCA IgA), which differed drastically between the two groups [67.7%vs. 5.5%, OR (95% confidence interval) = 36 (26.55-48.81),p <0.0001].HLA-Ballelic variation did not associate with seropositivity for anti-VCA IgA in either group. Results from our study show, more clearly than previously, the existence of a cluster of low-frequency and rareHLA-Bvariants conferring low, or very low risk to NPC, a phenomenon not observed in other ethnic groups. Our data shed new insights into genetic susceptibility to NPC in southern Chinese populations. Future independent studies are warranted to replicate the findings reported in our study.