对990个EBV基因组的荟萃分析识别出EBER2 SNP7048及其与HLA-A*11:01的交互作用驱动鼻咽癌风险

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中文摘要

背景： 鼻咽癌（NPC）是东亚和东南亚（SEA）的重大健康负担。虽然EBV感染是主要驱动因素，但导致NPC发生的特定病毒株及其在不同地理区域流行区与宿主遗传学的交互作用仍知之甚少。方法：我们对388株EBV分离株进行了全基因组测序，并在新加坡队列中匹配了宿主全外显子组测序。为确定这些发现的全球意义，我们在三个独立队列（新加坡、香港以及中国广东和广西省）中进行了荟萃GWAS和系统发育分析，共计990个EBV基因组。结果：我们的研究识别出携带EBER2位点核心变异（SNP7048）的高危EBV株是NPC风险的关键病毒决定因素，约占东南亚归因风险的68%。荟萃分析显示，这些病毒株在所有人群中均与NPC一致相关，解决了先前区域间的遗传不一致性。我们证明了这些EBV风险株与宿主HLA-A*11:01保护性等位基因之间存在强效协同交互作用；缺乏这种保护且携带高危株的个体NPC风险增加30.9倍。系统发育分析进一步揭示，这些高危谱系沿历史迁徙路线从中国南方克隆扩增而遍布东南亚。结论：这些发现确立NPC的发生是由特定高危EBV谱系的分布及其与宿主免疫易感性的协同交互作用所驱动。这为流行区NPC的精准人群筛查和早期诊断提供了明确的遗传学框架。

英文摘要

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.