Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection
Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection
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DOI：
10.1073/pnas.1115761109
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发表时间：
2012-01-24
影响因子：
11.1
通讯作者：
Gilad, Yoav
中科院分区：
文献类型：
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作者：
Barreiro, Luis B.;Tailleux, Ludovic;Gilad, Yoav
结核病（TB）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结核分枝杆菌（MTB），结核病的病原体，并且活动性疾病每年在全世界杀死近200万人。几条证据表明，结核病易感性的个体间差异具有遗传成分，但我们对潜在的遗传结构仍知之甚少。为了解决这个问题，我们进行了一个基因组范围内的定位研究的基因座，与功能变异的免疫反应，结核分枝杆菌。具体而言，我们的特点是转录和蛋白质表达水平和映射表达数量性状基因座（eQTL）在初级树突状细胞（DC）从65个人，之前和之后感染结核分枝杆菌。我们发现了198个响应eQTL，即与未处理或MTB感染的DC中的基因表达水平变化相关的基因座，但不是两者。这些响应eQTL与可能直接或间接影响宿主与MTB相互作用的自然调控变异相关。事实上，当我们将我们的数据与肺结核全基因组关联研究（GWAS）的结果相结合时，我们发现响应eQTL更可能与疾病遗传相关。因此，我们确定了一些候选位点，特别是包括MAPK磷酸酶DUSP 14，这是有希望的易感基因肺结核。
Tuberculosis (TB) is a major public health problem. One-third of the world's population is estimated to be infected with Mycobacterium tuberculosis (MTB), the etiological agent causing TB, and active disease kills nearly 2 million individuals worldwide every year. Several lines of evidence indicate that interindividual variation in susceptibility to TB has a heritable component, yet we still know little about the underlying genetic architecture. To address this, we performed a genome-wide mapping study of loci that are associated with functional variation in immune response to MTB. Specifically, we characterized transcript and protein expression levels and mapped expression quantitative trait loci (eQTL) in primary dendritic cells (DCs) from 65 individuals, before and after infection with MTB. We found 198 response eQTL, namely loci that were associated with variation in gene expression levels in either untreated or MTB-infected DCs, but not both. These response eQTL are associated with natural regulatory variation that likely affects (directly or indirectly) host interaction with MTB. Indeed, when we integrated our data with results from a genome-wide association study (GWAS) for pulmonary TB, we found that the response eQTL were more likely to be genetically associated with the disease. We thus identified a number of candidate loci, including the MAPK phosphatase DUSP14 in particular, that are promising susceptibility genes to pulmonary TB.