University of Groningen Recipient's Genetic R702W NOD2 Variant Is Associated with an Increased Risk of Bacterial Infections after Orthotopic Liver Transplantation Janse,

Introduction: Orthotopic liver transplantation (OLT) is accompanied by a significant postoperative infection risk. Immunosuppression to prevent rejection increases the susceptibility to infections, mainly by impairing the adaptive immune system. Genetic polymorphisms in the lectin complement pathway of the donor have recently been identified as important risk determinants of clinically significant bacterial infection (CSI) after OLT. Another genetic factor involved in innate immunity is NOD2, which was reported to be associated with increased risk of spontaneous bacterial peritonitis in cirrhotic patients. Methods: We assessed association of three genetic NOD2 variants (R702W, G908R and 3020insC) with increased risk of CSI after OLT. 288 OLT recipient-donor pairs from two tertiary referral centers were genotyped for the three NOD2 variants. The probability of CSI in relation to NOD2 gene variants was determined with cumulative incidence curves and log-rank analysis. Results: The R702W NOD2 variant in the recipient was associated with CSI after OLT. Eight out of 15 (53.3%) individuals with a mutated genotype compared to 80/273 (29.3%) with wild type genotype developed CSI (p=0.027, univariate cox regression), illustrated by a higher frequency of CSI after OLT over time (p=0.0003, log rank analysis). Multivariate analysis (including the donor lectin complement pathway profile) showed independence of this R702W NOD2 association from other risk factors (HR 2.0; p=0.04). The other NOD2 variants, G908R and 3020insC, in the recipient were not associated with CSI. There was no association with CSI after OLT for any of the NOD2 variants in the donor. Conclusion: The mutated NOD2 R702W genotype in the recipient is independently associated with an increased risk of bacterial infections after liver transplantation, indicating a predisposing role for this genetic factor impairing the recipient’s innate immune system. Citation: Janse M, de Rooij B-JF, van Hoek B, van den Berg AP, Porte RJ, et al. (2013) Recipient’s Genetic R702W NOD2 Variant Is Associated with an Increased Risk of Bacterial Infections after Orthotopic Liver Transplantation. PLoS ONE 8(8): e72617. doi:10.1371/journal.pone. 0072617 Editor: Valli De Re, Centro di Riferimento Oncologico, IRCCS National Cancer Institute, Italy Received April 7, 2013; Accepted July 11, 2013; Published August 19, 2013 Copyright: © 2013 Janse et al. 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 credited. Funding: RKW is supported by a clinical fellowship grant (90.700.281) from the Netherlands Organization for Scientific Research. BJFdR is supported by grants from The Netherlands Organisation for Health Research and Development (AGIKO 2010/15659/) and the Dutch Digestive Foundation (WO 07-18). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. * E-mail: H.W. Verspaget@lumc.nl ☯ These authors contributed equally to this work. ¶ These authors also contributed equally to this work. PLOS ONE | www.plosone. org 1 August 2013 | Volume 8 | Issue 8 | e72617