Mapping eQTLs that affect susceptibility to Tuberculosis

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），其是引起结核病（TB）的病原体，并且活动性疾病每年在全世界杀死近200万人。结核病的一系列治疗方法很快变得无效，因为这种药物很快就会产生耐药性。然而，令人惊讶的是，只有10%的感染者会发展成这种疾病。换句话说，虽然结核分枝杆菌很快对新药产生耐药性，但大约90%的人对感染具有天然耐药性（当没有被危害免疫系统的病原体（如艾滋病毒）共同感染时）。有几条证据表明，遗传因素导致了结核病易感性的个体间差异，包括观察到同卵双胞胎的结核病发病率比异卵双胞胎高得多。此外，多个罕见的单基因突变与高突变率也与分枝杆菌的易感性有关。然而，尽管结核病的遗传学研究已经确定了保护性免疫的重要途径，但对导致人群易感性差异的潜在遗传决定因素或机制知之甚少。在这里，我们建议使用经验和统计方法相结合，以确定基因和调节途径，有助于个体间和群体间的差异，结核分枝杆菌感染的免疫反应。具体而言，我们将研究Mtb感染后树突细胞免疫转录应答的个体间变异，并绘制与这种变异相关的遗传基因座（eQTL）。据我们所知，这将是第一个全基因组研究分子数量性状和相关遗传标记的变化，这些遗传标记是结核分枝杆菌感染免疫反应个体间变异的基础，最终是结核病易感性变异的基础。

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.