Mapping eQTLs that affect susceptibility to Tuberculosis

描述（由申请人提供）：结核病是一个重大的公共卫生问题。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，活动性疾病每年在全球造成近200万人死亡。由于结核病药物迅速产生耐药性，连续的结核病治疗很快就失效了。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抗性（当没有被损害免疫系统的病原体（如艾滋病毒）共同感染时）。一些证据表明，遗传因素导致了结核病易感性的个体差异，包括观察到同卵双胞胎在结核病发病率方面的一致性比异卵双胞胎高得多。此外，具有高外显率的多个罕见单基因突变也与分枝杆菌易感性有关。然而，尽管结核病的遗传研究已经确定了参与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，我们建议结合经验和统计方法来确定基因和调控途径，这些基因和调控途径有助于个体间和群体间对结核分枝杆菌感染的免疫反应的差异。具体来说，我们将研究结核分枝杆菌感染后树突状细胞免疫转录反应的个体间变异，并绘制与这种变异相关的遗传位点（eqtl）。据我们所知，这将是第一次对分子数量性状和相关遗传标记变异的全基因组研究，这些变异是对结核分枝杆菌感染免疫反应的个体间变异以及最终对结核的易感性变异的基础。

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.