Mapping eQTLs that affect susceptibility to Tuberculosis

绘制影响结核病易感性的 eQTL

基本信息

批准号：
8417751
负责人：
Yoav Gilad
金额：
$ 51.15万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8417751
关键词：
Affect African American Alternative Splicing Asses Caucasians Caucasoid Race Chromosome Mapping Data Dendritic Cells Disease Dizygotic Twins Exons Flow Cytometry Gene Expression Gene Mutation Genes Genetic Genetic Determinism Genetic Markers Genotype Genus Mycobacterium Goals HIV Immune Immune response Immune system Immunity Immunoglobulin Variable Region Individual Individual Differences Infection Link Maps Measures Memory Molecular Molecular Profiling Monozygotic Twinning Monozygotic twins Morbidity - disease rate Mycobacterium tuberculosis Pathway interactions Penetrance Pharmaceutical Preparations Play Population Predisposition Property Protocols documentation Public Health Quantitative Trait Loci Regulatory Pathway Resistance Resistance development Role Sampling Single Nucleotide Polymorphism Technology Tuberculosis Variant Virulent Work base cytokine fighting genome wide association study genome-wide insight interest killings molecular marker monocyte public health relevance research study response secondary infection trait tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): Tuberculosis is a major public health problem. One-third of the population of the world is estimated to be infected with Mycobacterium tuberculosis (Mtb), the etiological agent causing tuberculosis (TB), and active disease kills nearly 2 million individuals worldwide every year. Successions of treatments of TB have quickly become ineffective as the agent rapidly becomes resistant. However, strikingly, only 10% of infected individuals develop the disease. In other words, while Mtb quickly develops resistance to new drugs, roughly 90% of individuals are naturally resistant to infection (when not co-infected by agents, which compromise the immune system, such as HIV). Several lines of evidence indicate that genetic factors contribute to inter-individual differences in susceptibility to TB, including the observation that monozygotic twins have considerably higher concordance rates for tuberculosis morbidity than do dizygotic twins. In addition, multiple rare single-gene mutations with high penetrance have also been linked with susceptibility to mycobacteria. However, although genetic studies of TB have identified important pathways involved in protective immunity, very little is known about the underlying genetic determinants or mechanisms contributing for differences in susceptibility at the population level. Here, we propose to use a combination of empirical and statistical approaches to identify genes and regulatory pathways that contribute to inter-individual and inter-population variability in the immune response to Mycobacterium tuberculosis infection. Specifically, we will study inter- individual variation in the immune transcriptional response of dendritic cells following infection with Mtb, and map the genetic loci that are associated with such variation (eQTLs). To our knowledge, this will be the first genome-wide study of variation in molecular quantitative traits and associated genetic markers that underlie inter-individual variation in immune response to infection with Mtb, and ultimately variation in susceptibility to TB.

描述（由申请人提供）：结核病是一个主要的公共卫生问题。据估计，世界人口的三分之一被感染结核分枝杆菌（MTB），病因学剂，引起结核病（TB），活动疾病每年杀死近200万个人。随着试剂迅速变得抗性，TB的连续治疗迅速变得无效。但是，令人惊讶的是，只有10％的感染者发展出这种疾病。换句话说，虽然MTB很快就对新药产生了抵抗力，但大约90％的个体自然抗感染具有抵抗力（如果不受损害免疫系统（例如HIV）的毒剂的感染，例如HIV）。几条证据表明，遗传因素在对结核病的敏感性上有助于个体间的差异，包括观察到，单卵双胞胎的结核病发病率要比二唑双胞胎的一致性率要高得多。此外，多个具有高渗透率的稀有单基因突变也与对分枝杆菌的易感性有关。但是，尽管结核病的遗传研究已经确定了与保护性免疫有关的重要途径，但对于导致人口水平易感性差异的基本遗传决定因素或机制知之甚少。在这里，我们建议使用经验和统计方法的组合来鉴定基因和调节途径，这些途径在对结核分枝杆菌感染的免疫反应中有助于个体间和人群间的变异性。具体而言，我们将研究用MTB感染树突状细胞免疫转录反应的个体变异，并绘制与这种变异相关的遗传基因座（EQTL）。据我们所知，这将是对分子定量性状和相关遗传标记变异的首次全基因组研究，这些研究是对MTB感染的免疫反应的基础，并最终导致TB易感性变化。