Identification of Candidate Gene Polymorphisms Associated with Infectious Diseas

宿主与病毒的相互作用由宿主编码免疫反应元件的基因和病原体成功完成生命周期所需的宿主蛋白调节。一种鉴定多态性位点的候选基因方法正被用于鉴定在病毒感染发病机制中起作用的基因。这些基因座的鉴定为鉴定在病毒感染、复制、病毒组装和感染的免疫调节中起作用的宿主细胞成分提供了有价值的工具。确定宿主因素限制病毒疾病进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。民族/种族群体之间突变频率的差异也可以至少部分地解释艾滋病毒和乙型肝炎病毒和丙型肝炎病毒（乙型肝炎病毒和丙型肝炎病毒）的地理差异。我们正在调查宿主遗传变异在美国和中国HIV、HBV和HCV自然历史队列研究中超过7000名参与者的疾病进展中的作用。我们的方法是：1)从研究参与者身上建立细胞系作为DNA的可再生来源；2)鉴定候选基因的单核苷酸多态性（snp）或插入/删除（indel）突变；3)利用高通量基因分型方法筛选snp；4)使用分类和生存分析来测试基因型和疾病表型之间的关联。编码RANTES （HIV-1共受体的配体）的基因启动子区域的多态性与艾滋病进展的调节有关。单倍型分析表明，一个新的内含子变体要么跟踪功能位点，要么修改两个启动子变体的作用。在体外结合HIV-1的5种趋化因子受体编码基因的系统筛选中，我们在这些基因的功能区或编码区鉴定了6个snp。尽管这些标志物与HIV发病机制无关，但它们可能是哮喘和关节炎等炎症性疾病的重要标志物。候选基因方法已经确定了至少10种影响HIV感染和病理的遗传变异。虽然每种变异的影响都很小，但它们加起来约占长期艾滋病幸存者的30-50%。使用HIV-1的遗传分析作为具有遗传和环境成分的复杂疾病关联分析的模型，我们正在采用类似的策略来调查宿主遗传对感染肝炎病毒，HCV和HBV后结果的贡献。这些重要的人类病毒感染具有全球分布，在世界某些区域和某些危险群体中流行率极高，并造成相当大的发病率和死亡率。它们还与肝癌的风险增加有关，并且具有相似的（尽管不完全相同）风险因素。由于这些病毒的致病作用是高度可变的，不能完全用毒株差异或亚型来解释，因此暴露的不同结果似乎有遗传基础。我们目前正在收集患者进行病例对照研究，以确定影响这些重要病原体的病毒清除、肝硬化进展和感染抗性的候选基因。与艾滋病和肝炎相关的候选基因多态性鉴定

Host-viral interactions are modulated by host genes encoding immune response elements and by host proteins required for the successful completion of the pathogen's lifecycle. A candidate gene approach to identify polymorphic loci is being used to identify genes that have a role in viral infection pathogenesis. Identification of such loci provides a valuable tool for the identification of host-cellular components that are operative in viral infection, replication, viral assembly, and immune regulation of the infection. 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 mutation frequencies between ethnic/racial groups may also explain at least in part the geographical variation observed for the HIV and hepatitis viruses B and C (HBV and HCV). We are investigating the role of host genetic variation on disease progression in over 7000 participants enrolled in HIV, HBV and HCV natural history cohort studies in the USA and China. 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 (indel) mutations in candidate genes; 3) screen SNPs using high throughput genotyping methods; and 4) use categorical and survival analyses to test for associations between genotypes and disease phenotypes.Polymorphisms in the promoter region of the gene encoding RANTES, a ligand for the HIV-1 coreceptor, are associated with modulation of AIDS progression. Haplotype analysis has revealed that a novel intron variant is either tracking the functional site or modifies the effect of two promoter variants. In a systematic screen of genes encoding 5 chemokine receptors that bind to HIV-1 in vitro, we have identified 6 SNPs in functional or coding regions of the genes. Although these markers are not associated with HIV pathogenesis, they may be important markers in inflammatory diseases such as asthma and arthritis. The candidate gene approach has led to the identification of at least ten genetic variants that affect HIV infection and pathology. Although the effect of each of these variants is small, together they account for approximately 30-50% of long-term AIDS survivors.Using the genetic analysis of HIV-1 as a model for association analysis of complex diseases which have both genetic and environmental components, we are employing a similar strategy to investigate the host genetic contributions to outcomes following infection with the hepatitis viruses, HCV and HBV. These important human viral infections have global distributions and extremely high prevalence rate in some regions of the world and among certain risk groups and cause considerable morbidity and mortality. They are also associated with increased risk of liver cancer, and have similar, although not identical, risk factors. Because pathogenic effects of these viruses are highly variable and not fully explained by strain differences or subtypes, it is plausable that differential outcomes to exposure have a genetic basis. We are currently accruing patients for case control studies to identify candidate genes which effect viral clearance, progression to cirrhosis, and resistance to infection for these important pathogens. Identification of Candidate Gene Polymorphisms Associated with AIDS and Hepatitis