THE GENETICS OF TUBERCULOSIS PATHOGENESIS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 结核病（TB）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的作用，但迄今为止的研究一直不一致，尚未出现全面的遗传模型。 以前的遗传学研究的局限性是，他们只分析了结核病的二元性状，这并不能反映疾病的异质性。 此外，这些研究没有考虑到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遗传率的估计。 我们在乌干达的结核病流行社区进行了一项家庭接触研究。 以前，我们估计了三种细胞因子作为结核病内表型的遗传性：干扰素-γ、肿瘤坏死因子-α（TNF）和转化生长因子-β。 使用标准的遗传力估计方法和通径分析，我们发现TNF具有较高的遗传力（66%）和共享环境的影响很小。 最近，我们完成了全基因组连锁扫描。 该分析确定了两个与结核病相关的区域，处于提示水平（p<.0001），这些区域的精细绘图分析正在进行中。 我们还观察到两个新区域与对M.肺结核感染。 进一步的分析将包括这些区域以及候选基因通路的精细定位。

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. Recently, we have completed a whole-genome linkage scan. This analysis identified two regions linked to TB at the suggestive level (p<.0001), fine mapping analysis of these regions is ongoing. We also observed suggestive linkage between two novel regions and resistance to M. tuberculosis infection. Further analyses will include fine mapping of these regions as well as candidate gene pathways.