Genetic Studies of Human Susceptibility to Tuberculosis

描述（由申请人提供） 结核病（TB）是目前和历史上一个巨大的公共卫生问题。 问题.目前世界上大约三分之一的人口 感染结核分枝杆菌（M.结核病）和结核病占 超过25%的可预防成人死亡。尽管感染率很高 在结核病患者中，只有约10%的人感染了结核杆菌， TB.有证据表明，活动性结核病的进展受到宿主的影响。 遗传因素例如，结核病的流行病学表明， 选择在引入M.结核病对人口的影响; 遗传易感个体屈服于感染， 有抵抗力的个体存活下来繁殖。 同时，双胞胎研究表明， 与异卵双胞胎相比，同卵双胞胎的结核病一致率更高 双胞胎分枝杆菌感染的小鼠模型已经鉴定出几种 潜在的易感基因位点，如Nramp1基因，以及 几种细胞因子和细胞因子受体基因。以家庭为基础的联系研究， 对人类候选基因的病例对照研究表明， 与人类结核病发展相关的其他基因。鉴于这些 观察，我们提出了一个以家庭为基础的候选基因的关联研究 结核病易感性的研究。为了实现识别基因影响的目标， 我们特别建议：1）确定1,000名父母， 儿童三合会（500名白人，500名非洲裔美国人）从北方和南方 卡罗莱纳进行结核病易感基因的遗传学研究。2)测试候选 前500个亲子三联体中的基因多个单核苷酸 多态性（SNP）将在每个基因中进行基因分型，并使用家族- 相关性测试;重大结果将在 剩下的500个三合会3)研究候选基因与 其他临床变量如PPD皮肤试验结果，疾病严重程度， 治疗复发和失败，以及存在肺外疾病。 四、 使用多变量评估基因-基因和基因-环境相互作用 模型和数据简化技术，如多因素维度 减少（MDR）方法。

DESCRIPTION (provided by applicant) Tuberculosis (TB) is currently and historically an enormous public health problem. Approximately one-third of the world's population are currently infected with Mycobacterium tuberculosis (M. tuberculosis) and TB accounts for over 25% of preventable adult deaths world-wide. Despite the high infection rate, only about 10% of people infected with M.tb ever become sick with active TB. Evidence suggests that progression to active TB is influenced by host genetic factors. For example, the epidemiology of TB suggests that genetic selection takes place after introduction of M. tuberculosis to the population; genetically susceptible individuals succumb to the infection and relatively resistant individuals survive to reproduce. As well, twin studies demonstrate higher concordance rates for TB among identical twins, compared to fraternal twins. Mouse models of mycobacterial infection have identified several potential susceptibility loci, such as the gene named Nramp1, as well as several cytokine and cytokine receptor genes. Family-based linkage studies and case-control studies of candidate genes in humans suggest roles for these and other genes associated with development of TB in humans. In light of these observations, we propose a family-based association study of candidate genes for TB susceptibility. To accomplish the goal of identifying genes influencing susceptibility to TB we specifically propose to: 1) Ascertain 1,000 parent- child triads (500 Caucasian, 500 African-American) from North and South Carolina for genetic studies of TB susceptibility genes. 2) Test candidate genes in the first 500 parent-child triads. Multiple single nucleotide polymorphisms (SNPs) will be genotyped in each gene and analyzed using family- based tests of association; significant results will be followed-up in the remaining 500 triads. 3) Examine the relationship between candidate genes and other clinical variables such as PPD skin test results, disease severity, treatment relapse and failure, and presence of extrapulmonary disease. 4) Evaluate gene-gene and gene-environment interactions using multivariable models and data reduction techniques such as the multifactor dimensionality reduction (MDR) method.