中国华南地区人群HLA-DQ基因序列特异性甲基化诱导EBV免疫逃逸及鼻咽癌发生的前瞻性流行病学研究

华南地区人群EBV慢性感染率高，但其具体的病因机制尚不清楚。我们发现华南人群中鼻咽癌（NPC）易感基因HLA-DQ及其密切相关的HLA-II类基因的7个高甲基化区域有促进EBV慢性感染作用。因此提出HLA-DQ高危型易诱导临近的HLA-II类基因甲基化，造成CD4+T细胞功能下降，促进病毒慢性转化及NPC发生的病因机制假说。在多个EBV不同感染状态人群中，抽提鼻咽细胞DNA，使用包括850K、HLA芯片、Sanger和BSP测序等多组学技术，全面筛选EBV慢性感染的易感基因，CIT分析基因序列特异性甲基化（ASM）介导基因型与病毒感染的因果关系；通过复查筛查队列，前瞻性验证不同HLA-DQ基因型、ASM与EBV感染，基因表达及NPC的风险。本研究为阐明华南人群EBV慢性感染率高的病因机制提供高级别证据，为开展EBV感染相关癌症预防提供途径。

The rate of chronic EBV infection in the population in South China is high, but the specific etiology is not clear. We found that seven hypermethylated regions of the nasopharyngeal carcinoma(NPC) susceptibility HLA-II gene and its closely related HLA-DQ genes in the south China population have a role in promoting chronic infection of EBV. Therefore, we propose a hypothesis that HLA-DQ high-risk type can easily induce the methylation of adjacent HLA-II genes, causing the decline of CD4+ T cell function and promoting the chronic transformation of the virus and the occurrence of NPC. We plan to extract nasopharyngeal cell DNA from the patients with different EBV infection statuses and utilize multi-omics technologies including 850K methylation array, HLA Array, Sanger sequencing and high-throughput BSP sequencing to comprehensively screen susceptible genes and allele-specific methylation (ASM) for EBV chronic infection. Causal inference test will be performed to evaluate the causal relationship between ASM-mediated genotypes and viral infection. Risks of EBV chronic infection and NPC occurrence associated with HLA-DQ genotypes and ASM are prospectively verified based on previously established screening cohorts. The proposed study will provide high-level scientific evidence for elucidating the etiology of chronic EBV infection with EBV and provides an approach to prevent cancer-related to EBV infection.