Meta-analysis of 990 EBV genomes identifies EBER2 SNP7048 and its interaction with HLA-A*11:01 driving nasopharyngeal carcinoma risk.

Authors

Ching-Yuan Wang, Fei Yao, Xinyi Zhang, Ling Wang, Yee Yen Sia, Enya Hui Wen Ong, Eugenia Li Ling Yeo, Andrea Nicole Rio, Chor Hiang Siow, Han Lee Goh, Zhi Kang Chin, Rachel Jia Xuan Ng, Ying Yu Tan, Javier Cher An Chee, Wei Keat Teo, Weiwei Zhai, Yanhong Chen, Miao Xu, Kwok Seng Loh, Wan-Teck Lim, Melvin Lee Kiang Chua, Joshua K Tay, Jianjun Liu

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 43. Pages e2617057123. Oct 27, 2026. Epub Oct 20, 2026.

Abstract

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-carrying a core variant in the EBER2 locus (SNP7048)-as 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.

PMID:
42900724
Bibliographic data and abstract were imported from PubMed on 21 Oct 2026.

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