Impact of Polymorphisms of TLR4/CD14 and TLR3 on Acute Rejection in Kidney Transplantation

Abstract

Background. Organ transplantation itself inevitably activates the innate immune system by toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the possible association between the TLR4/CD14 and TLR3 polymorphisms of donor-recipient pairs, and acute rejection after living donor kidney transplantation. Methods. TLR4 - 1607T/C (rs10759932), -2026A/G (rs1927914); CD14-159C/T (rs2569190); and TLR3 rs3775290, rs3775291, and rs3775296 were genotyped using DNA samples from 216 donor-recipient pairs of adult living donor kidney transplantation between January 1996 and July 2006. Dual luciferase reporter assay was performed to determine the functional significance of promoter single-nucleotide polymorphisms (SNPs) of TLR4. Results. Acute rejection occurred in 42 recipients (19.4%) of 216 adult transplant patients within I year. The genotype distributions of both recipient and donor TLR4 rs10759932 differed significantly between the control (no rejection) and acute rejection groups. For recipient rs10759932, the adjusted odds ratio for the TC+CC over TT genotype was 0.25 (95% confidence interval, 0.11-0.57; P=0.001). When the rs10759932 CC genotype was present in the recipient or donor, no episode of acute rejection occurred (Fisher's exact test, P=0.023). The presence of the rs10759932 C allele was associated with higher rejection-free survival rates (log-rank test, P=0.0053). However, there was no difference in transcriptional activity between wild-type and variant promoters of TLR4. In contrast to TLR4, SNPs of TLR3 or CD14 had no influence on acute rejection. Conclusion. These findings suggest the importance of TLR4 in the pathogenesis of acute rejection in kidney transplantation.