THE GENETICS OF TUBERCULOSIS PATHOGENESIS

结核病发病的遗传学

• 批准号: 8171711
• 负责人: Catherine Marie Stein
• 金额: $ 0.99万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171711
• 关键词: Accounting; Candidate Disease Gene; Communities; Computer Retrieval of Information on Scientific Projects Database; Disease; Disease susceptibility; Environment; Funding; Genetic; Genetic Models; Genome; Grant; Heritability; Heterogeneity; Household; Institution; Interferon Type II; Link; Maps; Methods; Pathogenesis; Pathway interactions; Public Health; Research; Research Personnel; Resistance; Resources; Risk; Role; Scanning; Source; Transforming Growth Factor beta; Tuberculosis; Tumor Necrosis Factor-alpha; Uganda; United States National Institutes of Health; cytokine; endophenotype; novel; trait

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 结核病（TB）是日益增长的公共卫生问题。 几项研究表明，宿主遗传学在疾病易感性中的作用，但迄今为止的研究尚未稳定，尚未出现全面的遗传模型。 以前的遗传研究的局限性是他们仅分析了二元性状结核病，这不反映疾病异质性。 此外，这些研究尚未考虑到家庭中共享环境对结核病风险的影响，这可能会夸大其遗传力的估计。 我们在乌干达的一个结核病社区进行了家庭联系研究。 以前，我们估计了三种细胞因子作为结核病的遗传性：干扰素 - 伽马，肿瘤坏死因子-Alpha（TNF）和转化生长因子β。 使用标准的遗传力估计方法和路径分析，我们发现TNF具有较高的遗传力（66％），并且对共享环境的影响很小。 最近，我们完成了全基因组链接扫描。 该分析确定了与TB相关的两个区域（p <.0001），对这些区域进行了精细的映射分析。 我们还观察到了两个新的区域之间的暗示性联系，并抗结核分枝杆菌感染。 进一步的分析将包括对这些区域以及候选基因途径的精细映射。