Pathway analysis of tuberculosis pathogenesis

结核病发病机制的通路分析

基本信息

批准号：
8514687
负责人：
Catherine Marie Stein
金额：
$ 31.28万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8514687
关键词：
2q21 5p13 Affect Africa South of the Sahara Candidate Disease Gene Cessation of life Chronic Clinical Complex Computer software Consensus Contracts Data Data Analyses Development Disease Environment Environmental Risk Factor Epidemiological Factors Epidemiology Equation Family Genes Genetic Genetic Predisposition to Disease Genetic Risk Genome Scan Goals HIV Health Household IFNGR1 gene Immune Immune response Immunologic Factors Immunologics Interleukin-10 Joints Knowledge Ligands Link Literature Malignant Neoplasms Maps Measurement Methods Microsatellite Repeats Modeling Mycobacterium tuberculosis Natural History Natural Immunity Outcome Pathogenesis Pathway Analysis Pathway interactions Patients Phenotype Play Population Study Prevalence Process Production Public Health Research Research Design Resistance Resistance to infection Risk Role Staging Statistical Methods TNFRSF1A gene Tuberculosis Uganda United States National Institutes of Health Work base clinical risk cytokine disorder risk genetic analysis genetic risk factor genome wide association study improved interdisciplinary approach latent infection model development novel pandemic disease prospective response therapeutic vaccine

项目摘要

DESCRIPTION (provided by applicant): Tuberculosis (TB), caused by M. tuberculosis (Mtb), is a significant, global public health problem, particularly in sub-Saharan Africa, where the prevalence of TB is increasing dramatically with the rise of the HIV pandemic. Previous studies provide strong evidence that host genetic factors contribute to the risk for TB disease; those studies identified potential candidate genes, but no consensus model for the genetic susceptibility to TB has yet emerged, and no studies have examined genetic influences on the early stages of Mtb infection. The present proposal utilizes patients and data collected through the Tuberculosis Research Unit (TBRU) NIH contract. Since 1995, we have been conducting a household contact study in Uganda where we are able to observe genetic and environmental risk factors for chronic Mtb infection and active TB disease. Our previous work has focused on genetic influences on the immune response and the spectrum of natural history of Mtb infection. We have shown that the TNFR1, IL10, and IFNGR1 genes are associated with TB but not resistance to Mtb infection. We have recently completed a genome scan that identified novel chromosomal regions, 2q21-2q24 and 5p13- 5q22, linked to resistance to Mtb. We have also identified innate immune response variables associated with progression to TB disease, but have not assessed immune factors associated with resistance to Mtb infection. Our preliminary results suggest that genetic and immune factors associated with resistance to Mtb infection versus TB disease development differ. Furthermore, we hypothesize that the complex interrelationships between host genes, innate immune response, and epidemiological factors combine to influence Mtb infection and progression to TB disease. To fully examine this complex network of genes and immune factors, we propose to construct a comprehensive pathway model. To this end, we propose three aims. First, we propose to fine map these novel chromosomal regions and analyze candidate genes in key immune pathways to identify genes associated with resistance to Mtb infection. Second, we propose to analyze a number of cytokines in response to innate immunity ligands to identify aspects of the innate immune response associated with resistance to Mtb infection. Third, we have developed a structural equation modeling framework appropriate for the analysis of family data, and we propose to analyze this data with that model and make software publicly available. We will analyze genetic and immunologic predictors of resistance to Mtb infection within the long-standing household contact study. This will also provide the first examination of resistance to Mtb infection; because of our thorough study design, we are uniquely poised to analyze this novel phenotype. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is a disease with great public health importance, with one-third of the world infected by M. tuberculosis (Mtb), and almost 8 million new cases of TB occur annually with 2 million deaths attributed to TB each year. Previous studies have shown a role for both genetic and immunologic factors that predispose to progression from Mtb infection to active TB disease, but these factors have not been analyzed simultaneously and have not identified factors associated with the "healthy" uninfected state. Findings of this project will expand knowledge of the joint genetic, epidemiologic, and immunologic influences on Mtb infection and TB disease, which will facilitate the development of improved vaccines and therapeutics.

描述（由申请人提供）：结核分枝杆菌（MTB）引起的结核病（TB）是一个重大的全球公共卫生问题，尤其是在撒哈拉以南非洲，在撒哈拉以南非洲，TB的患病率随着随着升高的兴趣而急剧上升。艾滋病毒大流行。先前的研究提供了有力的证据，表明宿主遗传因素有助于结核病疾病的风险。这些研究确定了潜在的候选基因，但是尚未出现针对结核病遗传易感性的共识模型，并且尚无研究检查在MTB感染的早期阶段的遗传影响。本提案利用通过结核病研究部（TBRU）NIH合同收集的患者和数据。自1995年以来，我们一直在乌干达进行一项家庭接触研究，我们能够观察到慢性MTB感染和活动性结核病疾病的遗传和环境风险因素。我们以前的工作集中在对MTB感染的免疫反应和自然历史谱系的遗传影响上。我们已经表明，TNFR1，IL10和IFNGR1基因与TB相关，但对MTB感染没有抗性。我们最近完成了一项基因组扫描，该扫描确定了新型染色体区域，即2q21-2q24和5p13-5q22，与对MTB的抗性有关。我们还确定了与TB疾病进展相关的先天免疫反应变量，但尚未评估与MTB感染抗性相关的免疫因子。我们的初步结果表明，与MTB感染相对于结核病疾病发育的耐药性相关的遗传和免疫因子不同。此外，我们假设宿主基因，先天免疫反应和流行病学因素之间的复杂相互关系结合起来，影响MTB感染并发展为结核病疾病。为了充分检查这个复杂的基因和免疫因素网络，我们建议构建一个综合途径模型。为此，我们提出了三个目标。首先，我们建议详细绘制这些新型染色体区域，并分析关键免疫途径中的候选基因，以鉴定与对MTB感染抗性相关的基因。其次，我们建议分析对先天免疫配体的许多细胞因子，以识别与MTB感染抗性有关的先天免疫反应的各个方面。第三，我们已经开发了一个适合分析家庭数据的结构方程建模框架，我们建议使用该模型分析此数据并使软件公开可用。我们将在长期的家庭接触研究中分析抗MTB感染的遗传和免疫学预测指标。这还将提供对MTB感染的抗性的首次检查；由于我们的研究设计，我们有独特的准备来分析这种新型表型。公共卫生相关性：结核病（结核病）是一种非常重要的疾病，三分之一的世界感染了结核分枝杆菌（MTB），近800万例新的TB病例每年发生200万例死亡，归因于TB每年。先前的研究表明，遗传因素和免疫因子的作用都使人联想到从MTB感染到活动性结核病疾病的发展，但是这些因素尚未同时分析，并且尚未确定与“健康”未感染状态相关的因素。该项目的发现将扩大对MTB感染和TB疾病的联合遗传，流行病学和免疫学影响的了解，这将有助于改善疫苗和治疗剂的发展。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

strum: an R package for structural modeling of latent variables for general pedigrees.

strum：一个 R 包，用于对一般谱系的潜在变量进行结构建模。

DOI：
10.1186/s12863-015-0190-3
发表时间：
2015
期刊：
BMC genetics
影响因子：
2.9
作者：
Song,YeunjooE;Stein,CatherineM;Morris,NathanJ
通讯作者：
Morris,NathanJ

Joint modeling of longitudinal data and discrete-time survival outcome.

DOI：
10.1177/0962280213490342
发表时间：
2016-08
期刊：
Statistical methods in medical research
影响因子：
2.3
作者：
Qiu F;Stein CM;Elston RC;Tuberculosis Research Unit (TBRU)
通讯作者：
Tuberculosis Research Unit (TBRU)

Novel polymorphisms in TICAM2 and NOD1 associated with tuberculosis progression phenotypes in Ethiopian populations.

DOI：
10.1017/gheg.2017.17
发表时间：
2018
期刊：
Global health, epidemiology and genomics
影响因子：
0
作者：
Mekonnen E;Bekele E;Stein CM
通讯作者：
Stein CM

Structural equation modeling with latent variables for longitudinal blood pressure traits using general pedigrees.

使用一般谱系对纵向血压特征的潜在变量进行结构方程建模。

DOI：
10.1186/s12919-016-0047-4
发表时间：
2016
期刊：
BMC proceedings
影响因子：
0
作者：
Song,YeunjooE;Morris,NathanJ;Stein,CatherineM
通讯作者：
Stein,CatherineM

Tuberculosis as a complex trait: impact of genetic epidemiological study design.

结核病作为一种复杂的特征：遗传流行病学研究设计的影响。

DOI：
10.1007/s00335-010-9301-7
发表时间：
2011
期刊：
Mammalian genome : official journal of the International Mammalian Genome Society
影响因子：
0
作者：
Stein,CatherineM;Baker,AllisonR
通讯作者：
Baker,AllisonR