GENETIC EPIDEMIOLOGY OF TUBERCULOSIS SUSCEPTIBILITY

描述：（改编自申请人摘要）。 长期目标 这项研究的目的是确定人类基因在多大程度上 变异性有助于结核病的易感性和结核病的特征。 导致的疾病。 为了避免与以前的工作相关的陷阱， 这些问题将在核苷酸水平上进行研究， 大约250-300名儿科患者被分配到精确定义的 临床疾病分类。 研究人群为儿童TB 居住在德克萨斯州休斯顿的患者，该城市报告的 美国的儿童结核病基因分型策略， 在这项国际合作研究的实验室里， 组将用于确定儿童患者中结核病的相关性 在四个候选易感基因座中存在多态性：NRAMPI（编码 一种巨噬细胞膜蛋白，在介导小鼠对 TNFA（编码细胞因子肿瘤坏死因子-α）; MBL（编码甘露糖结合蛋白）和VDR（编码维生素D 受体）。 新的、最先进的分子策略也将被用于 进行全基因组筛选，以确定以前与 人类结核病易感性。 将分析所有结核分枝杆菌病例分离株 从分子水平来检验不同病原体基因型是 与某些宿主基因型非随机相关（即，的潜在 宿主-病原基因型组合在介导疾病性状中的作用 将予以审查）。 通过对寄主和病原体分子数据的结合分析， 与患病患者的临床病理相关性， 旨在为宿主-病原体关系提供新的见解。

DESCRIPTION: (Adapted from Applicant's Abstract). The long-tern objective of this research is to determine the extent to which human genetic variability contributes to TB susceptibility and to the character of the resulting disease. To avoid pitfalls associated with previous work in this field, these questions will be examined at the nucleotide level in approximately 250-300 pediatric patients assigned to precisely defined clinical disease categories. The study population will be pediatric TB patients living in Houston, TX, a city with the highest reported rate of childhood TB in the U.S. Genotyping strategies, already employed successfully in the laboratories of this international collaborative study group will be used to determine the association of TB in pediatric patients with polymorphisms in four candidate susceptibility loci: NRAMPI (encoding a macrophage membrane protein critical in mediating murine susceptibility to BCG infection); TNFA (encoding the cytokine tumor necrosis factor-alpha); MBL (encoding mannose binding protein); and VDR (encoding the Vitamin D receptor). New, state-of-the-art molecular strategies will also be used to conduct a genome-wide screen to identify loci not previously associated with human TB susceptibility. All M.tuberculosis case isolates will be analyzed molecularly to test the hypothesis that distinct pathogen genotypes are non-randomly associated with certain host genotypes (i.e., the potential role of host-pathogen genotypic combinations in mediating disease character will be examined). By wedding analysis of host and pathogen molecular data with clinicopathologic correlates of afflicted patients, the proposed study is intended to contribute new insights into host-pathogen relationships.