HERITABILITY ANALYSIS OF INTERMEDIATE PHENOTYPES OF TUBERCULOSIS: AIDS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。结核病是一个日益严重的全球公共卫生问题。一些研究表明宿主遗传学在疾病易感性中发挥了作用，但到目前为止，研究还不一致，还没有出现全面的遗传模型。以前的遗传学研究的一个局限性是，他们只分析了二元性状TB，这并不能反映疾病的异质性。此外，这些研究没有考虑家庭内共享环境对结核病风险的影响，这可能会错误地夸大对遗传性的估计。我们在乌干达一个结核病流行社区进行了一项家庭接触研究。在此之前，我们估计了三种细胞因子作为结核病内表型的遗传度：干扰素-γ、肿瘤坏死因子-α和转化生长因子-β。在该分析中，肿瘤坏死因子-α表现出较高的遗传度(68%)，我们对其进行通径分析和分离分析。通径分析表明，肿瘤坏死因子α是可遗传的(狭义遗传度=34-66%)；共享环境的影响很小(1-14%)，但可能涉及基因-环境交互作用。对肿瘤坏死因子α的分离分析表明，一个主基因模型解释了三分之一的表型变异，并提供了自然选择作用于该表型的假定证据。我们的数据进一步支持TNFpha作为结核病的内表型，因为它可能增加检测疾病易感基因的能力。我们目前正在对候选基因进行连锁和关联分析，基因组扫描也在进行中。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tuberculosis (TB) is a growing global public health problem. Several studies suggest a role for host genetics in disease susceptibility, but studies to date have been inconsistent and a comprehensive genetic model has not emerged. A limitation of previous genetic studies is that they only analyzed the binary trait TB, which does not reflect disease heterogeneity. Furthermore, these studies have not accounted for the influence of shared environment within households on TB risk, which may spuriously inflate estimates of heritability. We conducted a household contact study in a TB-endemic community in Uganda. Previously, we estimated the heritability of three cytokines as endophenotypes for TB: interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta. In that analysis, tumor necrosis factor-alpha demonstrated high (68%) heritability, and we followed it up with path and segregation analysis. Path analysis, conducted to assess the effect of shared environment, suggested that TNFalpha is heritable (narrow sense heritability = 34-66%); the effect of shared environment is minimal (1-14%), but gene-environment interaction may be involved. Segregation analysis of TNFalpha suggested a major gene model that explained one-third of the phenotypic variance, and provided putative evidence of natural selection acting on this phenotype. Our data further support TNFalpha as an endophenotype for TB, as it may increase power to detect disease-predisposing loci. We are currently conducting linkage and association analysis of candidate genes, and a genome scan is also underway.