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
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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