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：
8602810
负责人：
Yoav Gilad
金额：
$ 57.47万
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/8602810
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，世界上三分之一的人口感染了结核分枝杆菌 (Mtb)，这是导致结核病 (TB) 的病原体，活动性疾病每年导致全球近 200 万人死亡。由于结核病迅速产生耐药性，连续的结核病治疗很快就变得无效。然而，令人惊讶的是，只有 10% 的感染者会患上这种疾病。换句话说，虽然 Mtb 很快就会对新药产生耐药性，但大约 90% 的人对感染有天然的抵抗力（当没有同时感染损害免疫系统的病原体，如 HIV 时）。多项证据表明，遗传因素导致结核病易感性存在个体间差异，包括观察到同卵双胞胎的结核病发病率比异卵双胞胎要高得多。此外，多种罕见的高外显率单基因突变也与分枝杆菌易感性有关。然而，尽管结核病的遗传学研究已经确定了涉及保护性免疫的重要途径，但对导致人群水平易感性差异的潜在遗传决定因素或机制知之甚少。在这里，我们建议结合使用经验和统计方法来识别导致个体间和人群间结核分枝杆菌感染免疫反应变异的基因和调控途径。具体来说，我们将研究 Mtb 感染后树突状细胞免疫转录反应的个体间变异，并绘制与此类变异相关的遗传位点 (eQTL)。据我们所知，这将是第一个针对分子数量性状和相关遗传标记变异的全基因组研究，这些变异构成了对结核分枝杆菌感染的免疫反应的个体间变异，并最终导致结核病易感性的变异。