TLR1 Variant H305L Associated with Protection from Pulmonary Tuberculosis
Autor: | Ellis Owusu-Dabo, Norbert Reiling, Christian Meyer, Christa Ehmen, Rolf D. Horstmann, Thorsten Thye, Gerd Ruge |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
TIRAP Bacterial Diseases TLR 1 lcsh:Medicine Ghana Immune Receptors Biochemistry 0302 clinical medicine Gene Frequency Cell Signaling Genotype Medicine and Health Sciences Ethnicities Membrane Receptor Signaling Receptor lcsh:Science Toll-like Receptors Immune Response Disease Resistance African Americans Multidisciplinary Immune System Proteins biology Population groupings Immune Receptor Signaling Actinobacteria Infectious Diseases Research Article Signal Transduction Tuberculosis Immunology Genes Recessive Polymorphism Single Nucleotide Mycobacterium tuberculosis 03 medical and health sciences Immune system Leucine medicine Genetics Humans Genetic Predisposition to Disease Histidine Tuberculosis Pulmonary Genetic Association Studies Evolutionary Biology Innate immune system Bacteria Population Biology lcsh:R Organisms Biology and Life Sciences Proteins Cell Biology biology.organism_classification medicine.disease Tropical Diseases Toll-Like Receptor 1 030104 developmental biology Amino Acid Substitution Haplotypes Case-Control Studies lcsh:Q People and places Mycobacterium Tuberculosis Population Genetics 030215 immunology |
Zdroj: | PLoS ONE PLoS ONE, Vol 11, Iss 5, p e0156046 (2016) |
ISSN: | 1932-6203 |
Popis: | Toll like receptors (TLR) are key elements of the innate immune response and involved in the recognition of pathogens. To test common and rare TLR variants involved in susceptibility or resistance to infection with Mycobacterium tuberculosis we screened the exons of the genes encoding TLR 1, 2, 4, and the adaptor molecule TIRAP in more than 4500 tuberculosis (TB) cases and controls from Ghana. The analysis yielded 109 variants with possible functional impact, including 101 non-synonymous variants, three stop-variants, and five indels. Association analyses yielded a significant result for the TLR1 variant rs3923647, conferring strong protection against TB (Odds ratio [OR] 0.21, CI confidence interval [CI] 0.05–0.6, Pnominal 1 x 10−3) when applying a recessive model of inheritance. Replication analyses with an additional 3370 Ghanaian cases and control samples, and with data from a recent TB study of 533 African-Americans confirmed the protective effect and resulted in a combined OR of 0.19, with a nominal P value of 2.2 x 10−5, and a corrected P value of 4.1 x 10−4. The SNP is located near the binding pocket of TLR1 and causes an amino acid exchange from histidine to leucine at position 305. The observed effect may, therefore, be attributable to structural changes in the recognition site of the TLR1 molecule, allowing to bind those mycobacterial ligands which preferentially may induce a protective immune response. This is supported by the analysis of BCG-stimulated peripheral blood mononuclear cells, showing increased induction of the proinflammatory cytokine IFN-γ in carriers of the mutant TLR1 rs3923647 TT genotype, compared to the IFN-γ levels of individuals with the AT and AA genotypes. |
Databáze: | OpenAIRE |
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