THE GENETICS OF TUBERCULOSIS PATHOGENESIS: HIV

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 结核病是一个日益严重的公共卫生问题。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。使用标准遗传度估计方法和通径分析，我们发现肿瘤坏死因子具有很高的遗传度(66%)，而且共享环境的影响很小。对肿瘤坏死因子的分离分析表明，主基因效应解释了肿瘤坏死因子表型变异的三分之一。最近，我们完成了一项候选基因研究，发现IL10、TNFR1和IFNGR1中的SNPs与肿瘤坏死因子和结核病都有关联。此外，我们发现，TNFR1或结核病风险的影响会因艾滋病毒状况而改变。我们正在完成全基因组的连锁扫描，我们的分析表明，这些特征与先前描述的候选基因区域以及新区域之间存在关联。未来的分析将包括精细定位和分析新的候选基因途径。

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 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 yet 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 (TNF), and transforming growth factor-beta. Using both standard heritability estimation methods and path analysis, we found that TNF has a high heritability (66%) and very small influence of shared environment. Segregation analysis of TNF showed that a major gene effect explained one-third of the phenotypic variance of TNF. Recently, we have completed a candidate gene study, and found that SNPs in IL10, TNFR1, and IFNGR1 are associated with both TNF and TB. In addition, we found that the effect of TNFR1 or TB risk is modified by HIV status. We are completing a genome-wide linkage scan, and our analyses have shown linkage between these traits and previously characterized candidate gene regions as well as novel regions. Future analyses will include fine mapping and analysis of new candidate gene pathways.