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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\u2010IgA, in healthy males from NPC endemic area.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>HLA alleles of 1078 healthy males in southern China from the 21\u2010RCCP study were imputed using genome\u2010wide single nucleotide polymorphism data. EBV Zta\u2010IgA in blood samples were measured using an enzyme\u2010linked immunosorbent assay. Multiple logistic regression analysis was used to evaluate the effect of HLA allele on Zta\u2010IgA serological status and its potential joint association with smoking. The binding affinity for Zta\u2010peptide was predicted using NetMHCIIpan 4.0.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HLA\u2010DRB1*09:01 was found to be associated with a higher risk of Zta\u2010IgA seropositivity (odds ratio\u2009=\u20091.80, 95% confidence interval\u2009=\u20091.32\u20132.45; <jats:italic>p<\/jats:italic>\u2009=\u20091.82\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>). Compared with non\u2010smokers without HLA\u2010DRB1*09:01, the effect size increased to 2.19\u2010 and 3.70\u2010fold for the light and heavy smokers carrying HLA\u2010DRB1*09:01, respectively. Furthermore, HLA\u2010DRB1*09:01 showed a stronger binding affinity to Zta peptide than other HLA\u2010DRB1 alleles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study highlighted the pivotal role of genetic HLA variants in EBV reactivation and the etiology of NPC. Smokers with HLA\u2010DRB1*09:01 have a significantly higher risk of being Zta\u2010IgA seropositive, which indicates the necessity of smoking cessation in certain high\u2010risk populations and also provide clues for further research on the etiology of NPC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jgm.3375","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T05:59:25Z","timestamp":1624514365000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Association between HLA alleles and Epstein\u2013Barr virus Zta\u2010IgA serological status in healthy males from southern China"],"prefix":"10.1002","volume":"23","author":[{"given":"Lei\u2010Lei","family":"Yuan","sequence":"first","affiliation":[{"name":"School of Public Health Sun Yat\u2010sen University  Guangzhou China"},{"name":"State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Center  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang\u2010Mi","family":"Deng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Center  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen\u2010Qiong","family":"Xue","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Center  Guangzhou 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Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Center  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Da\u2010Wei","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Public Health Sun Yat\u2010sen University  Guangzhou China"},{"name":"State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Center  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Center  Guangzhou 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