Genetic Studies of Human Susceptibility to Tuberculosis

描述(由申请人提供) 结核病是当前和历史上一个巨大的公共卫生问题。 有问题。目前，世界上大约三分之一的人口 感染了结核分枝杆菌(结核分支杆菌)和结核病占 全世界超过25%的可预防的成人死亡。尽管感染率很高 在感染结核分枝杆菌的人中，只有大约10%的人曾因活动性疾病而患病。 结核病。有证据表明，进展为活动性结核病受宿主的影响 遗传因素。例如，结核病的流行病学表明，基因 在将结核分枝杆菌引入人群后进行选择； 遗传易感的个体会屈服于感染，并且相对 具有抵抗力的个体存活下来是为了繁殖。同样，双胞胎研究表明 与异卵双胞胎相比，同卵双胞胎的结核病符合率更高 双胞胎。分枝杆菌感染的小鼠模型已经确定了几种 潜在的易感基因，如名为Nramp1的基因，以及 几个细胞因子和细胞因子受体基因。以家庭为基础的联系研究和 对人类候选基因的病例对照研究表明，这些基因和 其他与人类结核病发展相关的基因。鉴于这些， 观察到，我们建议对候选基因进行基于家族的关联研究 结核病易感性。为了完成识别影响基因的目标 我们特别建议：1)确定1,000名父母- 来自南北的儿童黑社会(500名高加索人，500名非裔美国人) 卡罗莱纳州结核病易感基因的遗传学研究。2)考生 前500个亲子三合会中的基因。多个单核苷酸 多态(SNPs)将在每个基因中进行基因分型，并使用家系- 基于关联性测试；重要结果将在 剩下的500名三合会成员。3)考察候选基因与 其他临床变量，如PPD皮试结果，疾病严重程度， 治疗复发和失败，并存在肺外疾病。4) 用多变量评价基因与基因和基因与环境的相互作用 模型和数据约简技术，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.