Toll-like receptor (TLR) 2 promoter and intron 2 polymorphisms are associated with increased risk for spontaneous bacterial peritonitis in liver cirrhosis

Background & Aims: Toll-like receptor (TLR) 2 and nucleotide-binding oligomerisation domain (NOD) 2 recognize distinct pathogen-associated molecular patterns (PAMS) on the cell surface and in the cytoplasm, respectively. Since they may contribute to susceptibility to spontaneous bacterial peritonitis (SBP), we studied the effects of TLR2 gene variants on susceptibility for SBP in relation to the previously reported NOD2 alleles. Methods: Overall, 150 patients with liver cirrhosis and ascites were genotyped for TLR2 gene variants -16934 (rs4696480), Arg753Gln (rs5743708), Pro631His (rs5743704) and the TLR2 GT microsatellite polymorphism in intron 2. Patients were monitored for SBP over two years. TLR2 SNPs were identified by hybridization probe assays on a LightCycler system. Numbers of GT repeats were determined with an ABI310 sequencer and Genescan Analysis 2.1 software. Results: Fifty two patients (35%) had SBP. Unlike the TLR2 Arg753Gln and Pro631His mutations, SBP was significantly more frequent in patients with the TLR2-16934 TT genotype (38.5% vs. 15.3%; p = 0.002) and in carriers with two long tandem GT repeat alleles (>20) (53.8% vs. 25.5%; p = 0.001). A multivariate analysis confirmed TLR2 GT microsatellite polymorphism (OR = 3.8, p = 0.002) and NOD2 variants (OR = 3.3, p = 0.011) as independent predictors of SBP, and the simultaneous presence of both risk factors indicated a particularly high risk for SBP (OR = 11.3, p = 0.00002). Conclusions: Analogous to NOD2 risk variants, TLR2 polymorphisms indicate increased susceptibility toward SBP in cirrhotic patients with ascites, and the combination of the TLR2 GT micro-satellite polymorphism with at least one NOD2 risk variant enables improved identification of patients with a high risk for SBP. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.