Association between HLA alleles and Epstein–Barr virus Zta‐IgA serological status in healthy males from southern China

BACKGROUND: Nasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV) associated cancer, exhibits an extremely high incidence in southern Chinese. Given that human leukocyte antigen (HLA) plays critical roles in antigen presentation and relates to NPC susceptibility, it is speculated that certain HLA variants may affect EBV reactivation, which is a key pathogenic factor of NPC. Therefore, we attempted to identify HLA alleles associated with the indicator of EBV reactivation, Zta‐IgA, in healthy males from NPC endemic area. METHODS: HLA alleles of 1078 healthy males in southern China from the 21‐RCCP study were imputed using genome‐wide single nucleotide polymorphism data. EBV Zta‐IgA in blood samples were measured using an enzyme‐linked immunosorbent assay. Multiple logistic regression analysis was used to evaluate the effect of HLA allele on Zta‐IgA serological status and its potential joint association with smoking. The binding affinity for Zta‐peptide was predicted using NetMHCIIpan 4.0. RESULTS: HLA‐DRB1*09:01 was found to be associated with a higher risk of Zta‐IgA seropositivity (odds ratio = 1.80, 95% confidence interval = 1.32–2.45; p = 1.82 × 10(−4)). Compared with non‐smokers without HLA‐DRB1*09:01, the effect size increased to 2.19‐ and 3.70‐fold for the light and heavy smokers carrying HLA‐DRB1*09:01, respectively. Furthermore, HLA‐DRB1*09:01 showed a stronger binding affinity to Zta peptide than other HLA‐DRB1 alleles. CONCLUSIONS: Our study highlighted the pivotal role of genetic HLA variants in EBV reactivation and the etiology of NPC. Smokers with HLA‐DRB1*09:01 have a significantly higher risk of being Zta‐IgA seropositive, which indicates the necessity of smoking cessation in certain high‐risk populations and also provide clues for further research on the etiology of NPC.