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Toll-Like Receptor Family Polymorphisms Are Associated with Primary Renal Diseases but Not with Renal Outcomes Following Kidney Transplantation

Toll-like receptors (TLRs) play a crucial role in innate- and adaptive immunity. The TLR pathways were shown to play key functional roles in experimental acute and chronic kidney injury, including the allo-immune response after experimental renal transplantation. Data about the precise impact of TLR...

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Autores principales: Dessing, Mark C., Kers, Jesper, Damman, Jeffrey, Leuvenink, Henri G. D., van Goor, Harry, Hillebrands, Jan-Luuk, Hepkema, Bouke G., Snieder, Harold, van den Born, Jacob, de Borst, Martin H., Bakker, Stephan J. L., Navis, Gerjan J., Ploeg, Rutger J., Florquin, Sandrine, Seelen, Marc, Leemans, Jaklien C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596574/
https://www.ncbi.nlm.nih.gov/pubmed/26445497
http://dx.doi.org/10.1371/journal.pone.0139769
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author Dessing, Mark C.
Kers, Jesper
Damman, Jeffrey
Leuvenink, Henri G. D.
van Goor, Harry
Hillebrands, Jan-Luuk
Hepkema, Bouke G.
Snieder, Harold
van den Born, Jacob
de Borst, Martin H.
Bakker, Stephan J. L.
Navis, Gerjan J.
Ploeg, Rutger J.
Florquin, Sandrine
Seelen, Marc
Leemans, Jaklien C.
author_facet Dessing, Mark C.
Kers, Jesper
Damman, Jeffrey
Leuvenink, Henri G. D.
van Goor, Harry
Hillebrands, Jan-Luuk
Hepkema, Bouke G.
Snieder, Harold
van den Born, Jacob
de Borst, Martin H.
Bakker, Stephan J. L.
Navis, Gerjan J.
Ploeg, Rutger J.
Florquin, Sandrine
Seelen, Marc
Leemans, Jaklien C.
author_sort Dessing, Mark C.
collection PubMed
description Toll-like receptors (TLRs) play a crucial role in innate- and adaptive immunity. The TLR pathways were shown to play key functional roles in experimental acute and chronic kidney injury, including the allo-immune response after experimental renal transplantation. Data about the precise impact of TLRs and their negative regulators on human renal transplant outcomes however are limited and contradictory. We studied twelve non-synonymous single nucleotide polymorphisms (SNPs) of which eleven in TLR1-8 and one in SIGIRR in a final cohort comprising 1116 matching donors and recipients. TLR3 p.Leu412Phe and SIGIRR p.Gln312Arg significantly deviated from Hardy-Weinberg equilibrium and were excluded. The frequency distribution of the minor alleles of the remaining 10 TLR variants were compared between patients with end-stage renal disease (recipients) and controls (kidney donors) in a case-control study. Secondly, the associations between the minor allele frequency of the TLR variants and delayed graft function, biopsy-proven acute rejection and death-censored graft failure after transplantation were investigated with Cox regression. Carrier frequencies of the minor alleles of TLR1 p.His305Leu (OR = 4.79, 95% CI = 2.35–9.75, P = 0.0002), TLR1 p.Asn248Ser (OR = 1.26, 95% CI = 1.07–1.47, P = 0.04) and TLR8 p.Met1Val (OR = 1.37, 95% CI = 1.14–1.64, P = 0.008) were significantly higher in patients with ESRD, with little specificity for the underlying renal disease entity (adjusted for age, gender and donor-recipient relatedness). The minor allele frequency of none of the TLR variants significantly associated with the surrogate and definite outcomes, even when multivariable models were created that could account for TLR gene redundancy. In conclusion, genetic variants in TLR genes were associated with the prevalence of ESRD but not renal transplant outcomes. Therefore, our data suggests that specific TLR signaling routes might play a role in the final common pathway of primary renal injury. A role for TLR signaling in the context of renal transplantation is probably limited.
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spelling pubmed-45965742015-10-20 Toll-Like Receptor Family Polymorphisms Are Associated with Primary Renal Diseases but Not with Renal Outcomes Following Kidney Transplantation Dessing, Mark C. Kers, Jesper Damman, Jeffrey Leuvenink, Henri G. D. van Goor, Harry Hillebrands, Jan-Luuk Hepkema, Bouke G. Snieder, Harold van den Born, Jacob de Borst, Martin H. Bakker, Stephan J. L. Navis, Gerjan J. Ploeg, Rutger J. Florquin, Sandrine Seelen, Marc Leemans, Jaklien C. PLoS One Research Article Toll-like receptors (TLRs) play a crucial role in innate- and adaptive immunity. The TLR pathways were shown to play key functional roles in experimental acute and chronic kidney injury, including the allo-immune response after experimental renal transplantation. Data about the precise impact of TLRs and their negative regulators on human renal transplant outcomes however are limited and contradictory. We studied twelve non-synonymous single nucleotide polymorphisms (SNPs) of which eleven in TLR1-8 and one in SIGIRR in a final cohort comprising 1116 matching donors and recipients. TLR3 p.Leu412Phe and SIGIRR p.Gln312Arg significantly deviated from Hardy-Weinberg equilibrium and were excluded. The frequency distribution of the minor alleles of the remaining 10 TLR variants were compared between patients with end-stage renal disease (recipients) and controls (kidney donors) in a case-control study. Secondly, the associations between the minor allele frequency of the TLR variants and delayed graft function, biopsy-proven acute rejection and death-censored graft failure after transplantation were investigated with Cox regression. Carrier frequencies of the minor alleles of TLR1 p.His305Leu (OR = 4.79, 95% CI = 2.35–9.75, P = 0.0002), TLR1 p.Asn248Ser (OR = 1.26, 95% CI = 1.07–1.47, P = 0.04) and TLR8 p.Met1Val (OR = 1.37, 95% CI = 1.14–1.64, P = 0.008) were significantly higher in patients with ESRD, with little specificity for the underlying renal disease entity (adjusted for age, gender and donor-recipient relatedness). The minor allele frequency of none of the TLR variants significantly associated with the surrogate and definite outcomes, even when multivariable models were created that could account for TLR gene redundancy. In conclusion, genetic variants in TLR genes were associated with the prevalence of ESRD but not renal transplant outcomes. Therefore, our data suggests that specific TLR signaling routes might play a role in the final common pathway of primary renal injury. A role for TLR signaling in the context of renal transplantation is probably limited. Public Library of Science 2015-10-07 /pmc/articles/PMC4596574/ /pubmed/26445497 http://dx.doi.org/10.1371/journal.pone.0139769 Text en © 2015 Dessing et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Dessing, Mark C.
Kers, Jesper
Damman, Jeffrey
Leuvenink, Henri G. D.
van Goor, Harry
Hillebrands, Jan-Luuk
Hepkema, Bouke G.
Snieder, Harold
van den Born, Jacob
de Borst, Martin H.
Bakker, Stephan J. L.
Navis, Gerjan J.
Ploeg, Rutger J.
Florquin, Sandrine
Seelen, Marc
Leemans, Jaklien C.
Toll-Like Receptor Family Polymorphisms Are Associated with Primary Renal Diseases but Not with Renal Outcomes Following Kidney Transplantation
title Toll-Like Receptor Family Polymorphisms Are Associated with Primary Renal Diseases but Not with Renal Outcomes Following Kidney Transplantation
title_full Toll-Like Receptor Family Polymorphisms Are Associated with Primary Renal Diseases but Not with Renal Outcomes Following Kidney Transplantation
title_fullStr Toll-Like Receptor Family Polymorphisms Are Associated with Primary Renal Diseases but Not with Renal Outcomes Following Kidney Transplantation
title_full_unstemmed Toll-Like Receptor Family Polymorphisms Are Associated with Primary Renal Diseases but Not with Renal Outcomes Following Kidney Transplantation
title_short Toll-Like Receptor Family Polymorphisms Are Associated with Primary Renal Diseases but Not with Renal Outcomes Following Kidney Transplantation
title_sort toll-like receptor family polymorphisms are associated with primary renal diseases but not with renal outcomes following kidney transplantation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596574/
https://www.ncbi.nlm.nih.gov/pubmed/26445497
http://dx.doi.org/10.1371/journal.pone.0139769
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