IDENTIFICATION OF CANDIDATE GENE POLYMORPHISMS ASSOCIATED WITH INFECTIOUS DISEASE

我们正在利用候选基因的方法，以确定多态性位点，可能有一个在病毒感染和疾病进展的作用。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组分提供了有价值的工具。明确宿主因素限制病毒性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。不同种族/民族之间突变频率的差异也可以至少部分解释观察到的HIV和B型肝炎病毒（HBV）的地理变异。到目前为止，我们已经建立了近6000个细胞系，这些细胞系来自三个主要HIV风险群体（血友病患者、同性恋者和静脉注射吸毒者）的自然史队列。我们还启动了队列研究，以调查宿主遗传因素在丙型肝炎病毒（HCV）和HBV清除和病理中的作用。我们的做法是：1）建立来自研究参与者的细胞系作为DNA的可再生来源; 2）鉴定候选基因中的单核苷酸多态性（SNP）或插入/缺失（indel）突变; 3）在大群组以及病例和对照中筛选SNP;和4）使用分类和生存分析来测试基因型和表型之间的关联。到目前为止，我们的小组已经鉴定了6个基因，影响感染、进展为艾滋病的速度和特定的艾滋病结果。我们的研究小组已经确定了参与对艾滋病毒的免疫反应、病毒转录和病毒组装的基因中的几种变体，这些变体也被证明可以延缓或加速艾滋病的进展。虽然这些变异的影响很小，但它们加在一起约占艾滋病长期幸存者的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的关联分析的模型，我们正在采用类似的策略来调查宿主遗传对肝炎病毒、HCV和HBV感染后结果的贡献。这些重要的人类病毒感染具有全球分布，在世界某些地区和某些风险群体中的流行率极高，并造成相当大的发病率和死亡率。它们也与肝癌风险增加有关，并且具有相似但不相同的风险因素。这些病毒的致病作用是高度可变的，不能完全用菌株差异或亚型来解释。我们正在使用候选基因的方法来阐明在病毒清除、肝病进展和对这些重要病原体感染的抵抗力的风险组内观察到的广泛变异的遗传基础。与艾滋病相关的候选基因多态性的鉴定-候选基因，基因图谱，遗传易感性，艾滋病毒，微卫星，-人体组织，液体，细胞等。

We are utilizing a candidate gene approach to identify polymorphic loci that may have a role in viral infection and disease progression. 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 process will advance our understanding of viral pathogenesis and may lead to possible therapuetic interventions. Differences in mutation frequencies between ethnic/racial groups may also explain at least in part the geographical variation observed for both HIV and hepatitis B virus (HBV). To date we have established nearly 6000 cell lines from participants enrolled in natural history cohorts of the three major HIV risk groups, hemophiliacs, homosexuals, and intravenous drug users. We have also initiated cohort studies to investigate the role of host genetic factors in hepatitis C virus (HCV) and HBV clearance and pathology. Our approach has been: 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 in large cohorts and in cases and controls; and 4) use categorical and survival analyses to test for associations between genotypes and phenotype.To date our group has contributed to the identification of 6 genes that affect infection, the rate of progression to AIDS, and specific AIDS outcomes. Several variants in genes involved in immune response to HIV, viral transcription, and viral assembly have been identified by our group which also have been shown to delay or accelerate progression to AIDS. 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. The pathogenic effects of these viruses are highly variable and not fully explained by strain differences or subtypes. We are using a candidate gene approach to elucidate the genetic basis for the extensive variation observed within risk groups in viral clearance, liver disease progression, and resistance to infection for these important pathogens. Identification of Candidate Gene Polymorphisms Associated with AIDS - candidate genes, gene mapping, Genetic Susceptibility, HIV, microsatellites, - Human Tissues, Fluids, Cells, etc.