Abstract
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.
Highlights
Tuberculosis (TB) is a major public health problem
When we integrated our data with results from a genome-wide association study (GWAS) for pulmonary TB, we found that the response expression quantitative trait loci (eQTL)
Consistent with this notion, we found that the maturation of dendritic cells (DCs) after Mycobacterium tuberculosis (MTB) infection was accompanied by the strong upregulation of genes involved in immune responses (FDR < 10−26), including cytokine signaling, T-cell activation, and antigen presentation (FDR < 0.006; Fig. 1B and Dataset S2)
Summary
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. 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. The quest of the genetic determinants of susceptibility to TB at the population level has so far been primarily driven by case control studies of candidate genes. To identify such variants, we characterized genome-wide gene expression levels and mapped expression quantitative trait loci (eQTL) in untreated and MTB-infected monocyte-derived dendritic cells (DCs), from a panel of 65 healthy individuals of European descent. We provide a comprehensive view of regulatory mechanisms underlying variation in immune response to MTB infection
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