Toll-like Receptor 3 L412F Polymorphism May Protect Against Acute Graft Rejection in Adult Patients Undergoing Liver Transplantation for Hepatitis C-Related Cirrhosis M.J. Citores, I. Baños, A. Noblejas, S. Rosado, R. Castejon, and V. Cuervas-Mons ABSTRACT Liver transplantation activates the innate immune system by toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. The aim of this study was to evaluate the possible association of different single nucleotide polymor- phisms (SNPs) in several TLR genes with the incidence of acute graft rejection in liver transplant recipients for hepatitis C virus (HCV)-related cirrhosis. This is a single- center study of 100 adult patients who received a first whole only liver graft from deceased donors at our institution between 1988 and 2009 for cirrhosis due to HCV infection. We examined 10 SNPs in the TLR1 (S6021), TLR2 (R753Q), TLR3 (L412F), TLR4 (D299G and T399I), TLR5 (R392X), TLR6 (S249P), TLR7 (Q11L), and TLR9 (-1237T/C and -1486C/T) genes. Genotyping was carried out with the LightSNiP typing assay (TIB-MolBiol, Berlin, Germany) by analyzing the melting curves with the LightCycler 480 system (Roche Applied Science, Mannheim, Germany). Recipient ´ allelic and genotypic distributions for each SNP were compared among patients with and without acute rejection within the first 3 months after transplantation. We found the homozygous mutant TT genotype for TLR3 L412F was associated with a lower rate of acute rejection when compared with the homozygous wild-type genotype [odds ratio (OR) = 0.1, 95% confidence interval (95% CI) = 0.01– 0.86; P = .017], and showed a trend toward a lower graft rejection rate when compared with patients carrying one or two C alleles (OR = 0.15, 95% CI = 0.02–1.2, P = .05). No other associations with acute rejection rates were found for any other SNP evaluated. This preliminary study suggests an important role for SNP TLR3 L412F in acute rejection in liver transplant patients for HCV-related cirrhosis. Nevertheless, these findings must be prospectively validated in other cohorts of patients as well as in patients after liver transplantation for other etiologies than HCV. T OLL-LIKE RECEPTORS (TLRs) recognize specific molecular patterns derived from microbial compo- nents (exogenous ligands) and endogenous ligands re- leased by damaged cells, initiating the innate (and sub- sequently adaptive) immune response. 1 In solid organ transplantation, there is increasing evidence that TLR activation is involved in the innate immune recognition of an allograft, playing a critical role in allograft rejec- tion. 2–4 Since certain single nucleotide polymorphisms (SNPs) in TLRs have been demonstrated to impair immune responses to respective ligands, we hypothesized that genetic variations in the TLR system may affect the incidence of acute rejection after liver transplantation. To analyze such potential influences, we determined From the Laboratorio de Medicina Interna (M.J.C., S.R., R.C.), and Unidad de Trasplante Hepático (I.B., A.N., V.C.-M.) , Servi- cio de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain. This work has been partially supported by Instituto de Salud Carlos III (Madrid, Spain; PI08/1561), and by the “Cátedra de Patrocinio Universidad Autónoma de Madrid-Fundación Lair,” Universidad Autónoma de Madrid, Madrid, Spain. Address reprint requests to Marı´a J. Citores, BSc, PhD, Labo- ratorio de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, C/Joaquin Rodrigo 2, 28222 Majadahonda, Madrid, Spain. E-mail: mariajesus.citores@salud.madrid.org 0041-1345/11/$–see front matter © 2011 by Elsevier Inc. All rights reserved. doi:10.1016/j.transproceed.2011.05.011 360 Park Avenue South, New York, NY 10010-1710 2224 Transplantation Proceedings, 43, 2224 –2226 (2011)