{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:40:25Z","timestamp":1792521625762,"version":"4.5.0"},"reference-count":54,"publisher":"National Academy of Sciences","issue":"43","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Medical Research Council (NMRC) of Singapore","award":["OFLCG21Jun-0013"],"award-info":[{"award-number":["OFLCG21Jun-0013"]}]},{"name":"National Medical Research Council (NMRC) of Singapore","award":["OFLCG21Jun-0013"],"award-info":[{"award-number":["OFLCG21Jun-0013"]}]},{"DOI":"10.13039\/501100001348","name":"Agency for Science, Technology and Research","doi-asserted-by":"publisher","award":["Core Funding"],"award-info":[{"award-number":["Core Funding"]}],"id":[{"id":"10.13039\/501100001348","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,27]]},"abstract":"<jats:p>Nasopharyngeal carcinoma (NPC) is a major health burden in East and Southeast Asia (SEA). While EBV infection is a primary driver, the specific viral strains responsible for NPC development and their interaction with host genetics across geographically diverse endemic regions remain poorly understood. We performed a whole-genome sequencing of 388 EBV isolates and matched host whole-exome sequencing in a Singaporean cohort. To define the global significance of these findings, we conducted a meta-GWAS and phylogenetic analysis across three independent cohorts (Singapore, Hong Kong, and Guangdong and Guangxi provinces of China), totaling 990 EBV genomes. Our study identifies high-risk EBV strains\u2014carrying a core variant in the EBER2 locus (SNP7048)\u2014as the key viral determinator of NPC risk, accounting for approximately 68% of the attributable risk in SEA. Meta-analysis reveals these strains are consistently associated with NPC across all populations, resolving previous regional genetic discordances. We demonstrate a potent synergistic interaction between these EBV risk strains and the host HLA-A*11:01 protective allele; individuals lacking this protection while carrying a high-risk strain exhibit a 30.9-fold increase in NPC risk. Phylogenetic analysis further reveals that these high-risk lineages populated SEA through clonal expansion from Southern China, following historical migration routes. These findings establish that NPC development is driven by the distribution of specific high-risk EBV lineages and their synergistic interaction with host immune susceptibility. This provides a definitive genetic framework for precision population screening and early diagnosis of NPC in the endemic regions.<\/jats:p>","DOI":"10.1073\/pnas.2617057123","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:01:52Z","timestamp":1792519312000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Meta-analysis of 990 EBV genomes identifies EBER2 SNP7048 and its interaction with HLA-A*11:01 driving nasopharyngeal carcinoma risk"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3624-7880","authenticated-orcid":false,"given":"Ching-Yuan","family":"Wang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05k8wg936","id-type":"ROR","asserted-by":"publisher"}],"name":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street","place":["Genome, Singapore, Republic of 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Data from \u201cEBV whole genome sequencing from patients with nasopharyngeal carcinoma and other EBV-associated diseases and healthy controls.\u201d NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/bioproject?term=PRJNA522388. Deposited 14 February 2019."},{"key":"e_1_3_4_53_2","unstructured":"M. Xu . Data from \u201cGenome-wide profiling of Epstein-Barr virus integration by targeted sequencing in Epstein-Barr virus associated malignancies.\u201d NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA786275. Deposited 5 December 2021."},{"key":"e_1_3_4_54_2","unstructured":"Y. Chen . Data from \u201cEBV whole genome sequencing from patients with nasopharyngeal carcinoma and healthy controls.\u201d NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/bioproject?term=PRJNA1268153. 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