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PLoS Genet. 2017 Aug 9;13(8):e1006952. doi: 10.1371/journal.pgen.1006952. eCollection 2017 Aug.

Deciphering the genetic control of gene expression following Mycobacterium leprae antigen stimulation.

Manry J1,2,3, Nédélec Y4,5, Fava VM1,2,3, Cobat A6,7, Orlova M1,2,3, Thuc NV8, Thai VH8, Laval G9,10,11, Barreiro LB4,12, Schurr E1,2,3.

Author information

1
Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
2
McGill International TB Centre, McGill University, Montreal, Quebec, Canada.
3
Departments of Medicine and Human Genetics, McGill University, Montreal, Quebec, Canada.
4
Department of Genetics, CHU Sainte-Justine Research Centre, Montreal, Quebec, Canada.
5
Department of Biochemistry, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
6
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U.1163, Paris, France.
7
Paris Descartes University, Imagine Institute, Paris, France.
8
Hospital for Dermato-Venerology, Ho Chi Minh City, Vietnam.
9
Institut Pasteur, Unit of Human Evolutionary Genetics, Department of Genomes and Genetics, Paris, France.
10
Centre National de la Recherche Scientifique, URA3012, Paris, France.
11
Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris, France.
12
Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.

Abstract

Leprosy is a human infectious disease caused by Mycobacterium leprae. A strong host genetic contribution to leprosy susceptibility is well established. However, the modulation of the transcriptional response to infection and the mechanism(s) of disease control are poorly understood. To address this gap in knowledge of leprosy pathogenicity, we conducted a genome-wide search for expression quantitative trait loci (eQTL) that are associated with transcript variation before and after stimulation with M. leprae sonicate in whole blood cells. We show that M. leprae antigen stimulation mainly triggered the upregulation of immune related genes and that a substantial proportion of the differential gene expression is genetically controlled. Indeed, using stringent criteria, we identified 318 genes displaying cis-eQTL at an FDR of 0.01, including 66 genes displaying response-eQTL (reQTL), i.e. cis-eQTL that showed significant evidence for interaction with the M. leprae stimulus. Such reQTL correspond to regulatory variations that affect the interaction between human whole blood cells and M. leprae sonicate and, thus, likely between the human host and M. leprae bacilli. We found that reQTL were significantly enriched among binding sites of transcription factors that are activated in response to infection, and that they were enriched among single nucleotide polymorphisms (SNPs) associated with susceptibility to leprosy per se and Type-I Reaction, and seven of them have been targeted by recent positive selection. Our study suggested that natural selection shaped our genomic diversity to face pathogen exposure including M. leprae infection.

PMID:
28793313
PMCID:
PMC5565194
DOI:
10.1371/journal.pgen.1006952
[Indexed for MEDLINE]
Free PMC Article

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