Recipient’s Genetic R702W NOD2 Variant Is Associated with an Increased Risk of Bacterial Infections after Orthotopic Liver Transplantation

Abstract

IntroductionOrthotopic 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.MethodsWe 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.ResultsThe 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.ConclusionThe 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.

NOD2 gene variants confer risk for secondary sclerosing cholangitis in critically ill patients

“…We hypothesize that ICU patients carrying NOD2 variants might be predisposed to infectious complications, and hence may have an increased risk for the development of SSC in the setting of bile duct ischemia. This is in line with the observation that liver transplant recipients carrying the p.R702W variant are at increased risk of bacterial infections 18 . The distinct microbiological spectrum in bile, comprising predominantly Entercoccus faecium and faecalis , is consistent with previous reports 2 , 19 .…”

Genetic variants of innate immunity receptors are associated with mortality in cirrhotic patients with bacterial infection

“…Twenty‐one genetic variants in the MBL2, FCN2, MASP2, TLR2, TLR4 and NOD2 genes with known functional implications on protein level were evaluated . Genomic DNA was extracted from 10 mL EDTA peripheral blood samples.…”

“…Twenty-one genetic variants in the MBL2, FCN2, MASP2, TLR2, TLR4 and NOD2 genes with known functional implications on protein level were evaluated. [17][18][19][20] Genomic DNA was extracted from 10 mL EDTA peripheral blood samples. Genotype identification was performed at the Leiden University Medical Centre, Leiden, The Netherlands.…”