遗传和环境因素在鼻咽癌（NPC）发病中起重要作用。我们已证实人类白细胞抗原（HLA）基因多态性、EBV慢性激活和EBV高危亚型（RPMS1基因G>A突变）感染是其危险因素。还发现二者间存在相关关系。因此提出HLA介导EBV慢性感染和选择感染高危型EBV两条通路而致癌,并产生交互作用。但该假说尚缺乏流行病学证据。在前期建立6万NPC筛查及0.18万 EBV不同再激活人群队列基础上，拟开展多阶段研究。质谱技术检测白细胞HLA易感基因位点和唾液EBV亚型，定量PCR和基因表达谱芯片检测鼻咽脱落细胞EBVDNA和基因组表达。结合病因中介模型分析HLA-EBV协同作用的超额发病风险并分解其中的交互和中介作用大小。运用纵向数据模型分析EBV高危型在鼻咽粘膜癌变前感染规律及其对基因组影响。本研究为阐明基因-病毒交互作用与NPC发病关系提供前瞻性证据，有助揭示EBV高危亚型感染自然史及其致癌机制。

Genetic and environmental factors are causally related to nasopharyngeal carcinoma(NPC).We have identified that Human leukocyte antigen (HLA) polymorphisms, EBV chronic activation and high-risk EBV subtype (RPMS1 G>A variation) were the risk factors of NPC and also found that HLA genotype had related with different EBV subtype infections. Thus, we put forward the hypothesis that high-risk HLA genotype may interact and mediate EBV chronic infection and EBV high-risk subtype infection, and HLA high-risk genotypes collaborate with EBV to induce the occurrence of NPC. However, the hypothesis still has not been confirmed due to lack of epidemiological evidences. Based on the established NPC screening cohort (60000 participants) and the EBV different reactivation cohort (1800 participants), we plan to carry out a multi-phase study to explore the synergy function for NPC between HLA genetic and EBV infection. Genotyping of HLA SNPS and EBV high-risk SNP in saliva are tested using the Agena Bioscience Mass Array platform, EBV DNA and genome expression in the local nasopharynx are detected with real-time PCR and gene expression profile chip, respectively. Causal mediation analysis methods are used to perform joint interaction and mediation analysis of the effects of HLA genetic variants and EBV high-risk SNP or EBV chronic infection on NPC. Specifically, we decompose the total effect of each HLA genetic variant in the possible presence of the EBV genetic variant and EBV chronic infection on NPC into four components, with which the host variant may interact. With the longitudinal data analysis model, the affection for EBV high-risk subtype infection of nasopharyngeal mucosal and genome expression will be analyzed. This study will provide the prospective evidence for revealing the genetic-variant-by-EBV interaction and EBV mediation of genetic effects on NPC risk and help to illustrate the EBV high-risk subtype natural infection history and carcinogenic mechanism.