title: Toll-Like Receptor Family Polymorphisms Are Associated with Primary Renal Diseases but Not with Renal Outcomes Following Kidney Transplantation.
abstract: 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.
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Dessing
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jesper
authors.initials: J
authors.lastname: Kers
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Damman
authors.affiliation: Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Henri G D
authors.initials: HG
authors.lastname: Leuvenink
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Jan-Luuk
authors.initials: JL
authors.lastname: Hillebrands
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Bouke G
authors.initials: BG
authors.lastname: Hepkema
authors.affiliation: Department of Epidemiology, Unit of Genetic Epidemiology & Bioinformatics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Harold
authors.initials: H
authors.lastname: Snieder
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Jacob
authors.initials: J
authors.lastname: van den Born
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Martin H
authors.initials: MH
authors.lastname: de Borst
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Gerjan J
authors.initials: GJ
authors.lastname: Navis
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Rutger J
authors.initials: RJ
authors.lastname: Ploeg
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Seelen
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jaklien C
authors.initials: JC
authors.lastname: Leemans
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D051799:Delayed Graft Function / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006084:Graft Rejection / Q000235:genetics*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000628:therapy*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051193:Toll-Like Receptors / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D051193:Toll-Like Receptors