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We performed a case\u2013control study comparing genomic sequences of EBV isolated from saliva samples of 142 population carriers with those from primary tumour biopsies derived from 62 patients with NPC of Hong Kong. Cluster analysis discovered five EBV subgroups 1A\u2010C and 2A\u2010B amongst the population carriers in contrast to the predominance of 1A and \u2010B in the majority of NPC. Genome\u2010wide association study (GWAS) identified a panel of NPC\u2010associated single nucleotide polymorphisms (SNPs) and indels in the EBER locus. The most significant polymorphism, which can be found in 96.8% NPC cases and 40.1% population carriers of Hong Kong, is a four\u2010base\u2010deletion polymorphism downstream of EBER2 (EBER\u2010del) from coordinates 7188\u20137191 (<jats:italic>p<\/jats:italic>= 1.91 \u00d7 10<jats:sup>\u22127<\/jats:sup>). In addition, the predicted secondary structure of EBER2 is altered with likely functional consequence in nearly all NPC cases. Using the SNPs and indels associated with NPC, genetic risk score is assigned for each EBV variant. EBV variants with high genetic risk score are found to be much more prevalent in Hong Kong Chinese than individuals of other geographic regions and in NPC than other EBV\u2010associated cancers. We conclude that high risk EBV variants with polymorphisms in the EBER locus, designated as HKNPC\u2010EBERvar, are strongly associated with NPC. Further investigation of the biological function and potential clinical application of these newly identified polymorphisms in NPC and other EBV\u2010associated cancers is warranted.<\/jats:p>","DOI":"10.1002\/ijc.32049","type":"journal-article","created":{"date-parts":[[2018,12,10]],"date-time":"2018-12-10T16:33:57Z","timestamp":1544459637000},"page":"3031-3042","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["High risk Epstein\u2010Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma"],"prefix":"10.1002","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5572-8395","authenticated-orcid":false,"given":"Kwai Fung","family":"Hui","sequence":"first","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine The University of Hong Kong, Queen Mary Hospital Pokfulam, Hong Kong 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Shing Faculty of Medicine The University of Hong Kong, Queen Mary Hospital Pokfulam, Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki Pui","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine The University of Hong Kong, Queen Mary Hospital Pokfulam, Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hin","family":"Kwok","sequence":"additional","affiliation":[{"name":"Centre for Genomic Sciences The Hong Kong Jockey Club Building for Interdisciplinary Research, The University of Hong Kong Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pak C.","family":"Sham","sequence":"additional","affiliation":[{"name":"Center for Nasopharyngeal Carcinoma Research The University of Hong Kong Hong Kong SAR China"},{"name":"Centre for Genomic Sciences The Hong Kong Jockey Club Building for 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