Identification of Candidate Gene Polymorphisms Associate

宿主-病毒相互作用由宿主编码的免疫反应元件和完成病毒生命周期所需的蛋白质调节。一种候选基因方法正在被用于确定与人类癌症相关的四种病毒的病毒感染和发病机制的基因：乙肝病毒(乙肝病毒)和丙型肝炎病毒(丙型肝炎病毒)；肝细胞癌(肝癌)；爱泼斯坦-巴尔病毒(EBV)；鼻咽癌(NPC)；以及人类免疫缺陷病毒(HIV-1)；卡波西肉瘤(KS)和淋巴瘤。明确宿主因素限制病毒疾病过程的机制将促进我们对病毒发病机制的理解，并可能导致可能的治疗干预。种族之间、病毒株之间以及环境因素之间的等位基因和单倍型频率的差异，可能解释了艾滋病毒-1、EBV、乙肝病毒和丙型肝炎病毒的感染率和结果的地理差异。 我们正在研究宿主基因变异在疾病进展中的作用，研究对象是11,000多名参与者，这些参与者参加了美国和中国的艾滋病毒-1、乙肝和丙型肝炎自然病史队列和横断面研究。我们还利用一项病例对照研究来确定影响中国EBV感染患者鼻咽癌发展的宿主因素。我们的方法是：1)建立来自研究参与者的细胞系作为DNA的可再生来源；2)确定候选基因中的单核苷酸多态(SNPs)或插入/缺失突变；3)使用高通量基因分型方法筛选SNPs；以及4)使用分类和生存分析来测试基因类型和疾病表型之间的关联。 重要的进展包括(1)在编码趋化因子RANTES的基因的内含子1内鉴定出一个强调节区，RANTES是HIV-1辅助受体CCR5的配体。在调节区域内的SNP(命名为In1.1T/C)的等位基因被发现差异地结合核蛋白并调节转录：In1.1T等位基因强烈促进RANTES的转录，而In1.1C等位基因显著抑制这种增强。在37%的非裔美国人中发现的1.1C单倍型与加速发展为艾滋病和艾滋病相关死亡的速度有关。感染1.1C病毒的欧洲人和非洲裔美国人感染HIV-1的风险也更大。(3)STRL3-3K等位基因对非裔美国人具有保护作用，可延缓感染HIV-1的卡氏肺孢子虫肺炎患者的死亡。在对78例丙型肝炎病毒清除病例和156例匹配对照的初步候选基因分析中，观察到编码单核细胞趋化蛋白-1(MCP-1)基因的启动子变异具有显著的保护性关联。

Host-viral interactions are modulated by host-encoding immune response elements and proteins required for the completion of the viral life cycle. A candidate gene approach is being used to identify genes that have a role in viral infection and pathogenesis for four viruses associated with human cancers: the hepatitis viruses B (HBV) and C (HCV); hepatocellular carcinoma (HCC); Epstein-Barr virus (EBV); nasaopharyngeal carcinoma (NPC); and the human immune deficiency virus (HIV-1); Kaposi sarcoma (KS) and lymphoma. Defining the mechanisms by which host factors restrict viral disease processes will advance our understanding of viral pathogenesis and may lead to possible therapeutic interventions. Differences in allele and haplotype frequencies between racial groups and between viral strains together with environmental factors may explain the geographical variation in infection rates and outcomes observed for HIV-1, EBV, and the hepatitis viruses B and C. We are investigating the role of host genetic variation on disease progression in over 11,000 participants enrolled in HIV-1, HBV and HCV natural history cohort and cross-sectional studies in the USA and China. We are also utilizing a case-control study to identify host factors that influence the development of NPC in Chinese patients infected with EBV. Our approach has been to: 1) establish cell lines from study participants as a renewable source of DNA; 2) identify single nucleotide polymorphisms (SNPs) or insertion/deletion mutations in candidate genes; 3) screen SNPs using high throughput genotyping methods; and 4) use of categorical and survival analyses to test for associations between genotypes and disease phenotypes. Important advances include (1) the identification of a strong regulatory region within intron 1 in the gene encoding the chemokine RANTES, a ligand for the HIV-1 coreceptor, CCR5. Alleles of an SNP (named In1.1 T/C) within the regulator region were found to differentially bind nuclear proteins and regulate transcription: the In1.1 T allele strongly enhanced RANTES transcription, and In1.1 C allele significantly reduced this enhancement. In1.1 C-containing haplotypes, found in 37% of African Americans, were associated with an accelerated rate of progression to AIDS and AIDS-related death. Both European and African Americans carriers for In1.1 C were also at greater risk for HIV-1 infection. (3) The STRL3-3K allele was found to have a protective effect in African Americans by delaying death in HIV-1-infected individuals with Pneumocystis carinii pneumonia. In a preliminary candidate gene analysis of 78 HCV clearance cases and 156 matched controls, a significant protective association with a promoter variant in the gene encoding monocyte chemoattractant protein-1 (MCP-1) was observed.