No association of genetic variants in TLR4, TNF-α, IL10, IFN-γ, and IL37 in cytomegalovirus-positive renal allograft recipients with active CMV infection-Subanalysis of the prospective randomised VIPP study

Pascale Mazzola, Elke Schaeffeler, Oliver Witzke, Martin Nitschke, Volker Kliem, Max Zortel, Eva-Maria Wagner, Matthias Schwab, Ingeborg A Hauser, Pascale Mazzola, Elke Schaeffeler, Oliver Witzke, Martin Nitschke, Volker Kliem, Max Zortel, Eva-Maria Wagner, Matthias Schwab, Ingeborg A Hauser

Abstract

Background: Cytomegalovirus (CMV) infection is amongst the most important factors complicating solid organ transplantation. In a large prospective randomized clinical trial, valganciclovir prophylaxis reduced the occurrence of CMV infection and disease compared with preemptive therapy in CMV-positive renal allograft recipients (VIPP study; NCT00372229). Here, we present a subanalysis of the VIPP study, investigating single nucleotide polymorphisms (SNPs) in immune-response-related genes and their association with active CMV infection, CMV disease, graft loss or death, rejection, infections, and leukopenia.

Methods: Based on literature research ten SNPs were analyzed for TLR4, three for IFN-γ, six for IL10, nine for IL37, and two for TNF-α. An asymptotic independence test (Cochran-Armitage trend test) was used to examine associations between SNPs and the occurrence of CMV infection or other negative outcomes. Statistical significance was defined as p<0.05 and Bonferroni correction for multiple testing was performed.

Results: SNPs were analyzed on 116 blood samples. No associations were found between the analyzed SNPs and the occurrence of CMV infection, rejection and leukopenia in all patients. For IL37 rs2723186, an association with CMV disease (p = 0.0499), for IL10 rs1800872, with graft loss or death (p = 0.0207) and for IL10 rs3024496, with infections (p = 0.0258) was observed in all patients, however did not hold true after correction for multiple testing.

Conclusion: The study did not reveal significant associations between the analyzed SNPs and the occurrence of negative outcomes in CMV-positive renal transplant recipients after correction for multiple testing. The results of this association analysis may be of use in guiding future research efforts.

Conflict of interest statement

OW has received research grants for clinical studies, speaker’s fees, honoraria and travel expenses from Amgen, Astellas, Bristol-Myers Squibb, Chiesi, Hexal, Janssen-Cilag, MSD, Novartis, Roche, Pfizer, and Sanofi. MN has received research grant for clinical studies, speaker´s fees, honoraria and travel expenses form Alexion, Roche, Otsuka and Sanofi. VK has received honoraria for lectures from Astellas, DaVita, and Chiesi. MZ and EW are employees of Roche Pharma AG. IAH served as advisory board member for the study and received speaker’s honoraria and travel grants from Astellas, Biotest, Novartis, Roche Pharma, and Sanofi during the last 36 months. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Disposition of patients and samples…
Fig 1. Disposition of patients and samples analyzed.
SNP, single nucleotide polymorphism; VIPP, ValgancIclovir Prophylaxis versus Preemptive therapy in cytomegalovirus-positive renal allograft recipients.

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