TLR1 Variant H305L Associated with Protection from Pulmonary Tuberculosis.
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, a...
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| Format: | Article |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4877073?pdf=render |
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| author | Christian G Meyer Norbert Reiling Christa Ehmen Gerd Ruge Ellis Owusu-Dabo Rolf D Horstmann Thorsten Thye |
| author_facet | Christian G Meyer Norbert Reiling Christa Ehmen Gerd Ruge Ellis Owusu-Dabo Rolf D Horstmann Thorsten Thye |
| author_sort | Christian G Meyer |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T11:40:08Z |
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| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T11:40:08Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-da2ed85bbb0a4379bd758ad52931cb892022-12-22T02:48:20ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01115e015604610.1371/journal.pone.0156046TLR1 Variant H305L Associated with Protection from Pulmonary Tuberculosis.Christian G MeyerNorbert ReilingChrista EhmenGerd RugeEllis Owusu-DaboRolf D HorstmannThorsten ThyeToll 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.http://europepmc.org/articles/PMC4877073?pdf=render |
| spellingShingle | Christian G Meyer Norbert Reiling Christa Ehmen Gerd Ruge Ellis Owusu-Dabo Rolf D Horstmann Thorsten Thye TLR1 Variant H305L Associated with Protection from Pulmonary Tuberculosis. PLoS ONE |
| title | TLR1 Variant H305L Associated with Protection from Pulmonary Tuberculosis. |
| title_full | TLR1 Variant H305L Associated with Protection from Pulmonary Tuberculosis. |
| title_fullStr | TLR1 Variant H305L Associated with Protection from Pulmonary Tuberculosis. |
| title_full_unstemmed | TLR1 Variant H305L Associated with Protection from Pulmonary Tuberculosis. |
| title_short | TLR1 Variant H305L Associated with Protection from Pulmonary Tuberculosis. |
| title_sort | tlr1 variant h305l associated with protection from pulmonary tuberculosis |
| url | http://europepmc.org/articles/PMC4877073?pdf=render |
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