Poster Session A
Sunday, 19 April, 2015 - 19:00Genetic Modifiers of Immune Reactivity to a Human Pathogenic Mycobacterium
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 and Departments of Medicine and Human Genetics, McGill University, Montreal, Quebec, Canada; 3. Sainte-Justine Hospital Research Centre, Montreal, Quebec H3T 1C5, Canada; 4. Department of Biochemistry, Faculty of Medicine, University of Montreal, Montreal, Quebec H3T 1J4, Canada; 5. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, U.1163, Paris 75015, France; 6. Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec H3T 1J4, Canada.
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 of disease control are poorly understood. To address this gap in knowledge of leprosy pathogenicity, we conducted a genome-wide search for loci that are associated with transcript variation – expressed quantitative trait loci (eQTLs) – before and after stimulation with Mycobacterium leprae sonicate in whole blood cells from 54 unrelated leprosy patients from Vietnam.
Among 12043 tested genes, we found 6787 as being significantly up- or down-regulated. Gene ontology (GO) enrichment analysis on differentially expressed genes (DEG) allowed us to confirm that the vast majority of significant enrichments were related to the immune response, including genes that had previously been associated with leprosy (e.g. TNF is in the top 15 of the most DEG). We then identified 36700 cis-eQTLs for 818 genes, including 5784 for 33 genes associated with the “immune response” GO term. Interestingly, most of these “immune response” eQTLs (>95%) were eQTLs for genes in the HLA region. In addition, we found 7814 eQTLs as being specific to stimulated or to non-stimulated cells but not to both conditions. Of those, we found 336 response eQTLs for genes associated with the “immune response” GO term including 265 for HLA genes. This finding is concordant with the results of our genome-wide association study, which had identified the HLA system as an important genetic risk factor of disease. The response eQTLs correspond to regulatory variations that likely affect the interaction between human whole blood cells and M. leprae sonicate, and thus likely between the human host and M. leprae themselves. Remarkably, ADCY3 – previously identified as a leprosy type-I reaction signature gene – was one of the genes presenting the highest number of response eQTLs (present only after stimulation) as well as one of the highest up-regulations of gene expression. On the contrary, RNASE6 – known to have strong antimicrobial activity – had eQTLs specific to non-stimulated cells and underwent one of the strongest down-regulations after stimulation.
Given their association with changes in the immune response to M. leprae sonicate, these response eQTLs represent promising genetic candidates for susceptibility or resistance to leprosy and show the functional consequence of genetic risk factors for disease. Importantly, our study identified novel, hitherto unknown pathways of host responsiveness to M. leprae and substantially increases our understanding of leprosy pathogenicity.