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 TLR2gene variants on susceptibility for SBP in relation to the previously reported NOD2alleles. Methods Overall, 150 patients with liver cirrhosis and ascites were genotyped for TLR2gene variants −16934 (rs4696480), Arg753Gln (rs5743708), Pro631His (rs5743704) and the TLR2GT microsatellite polymorphism in intron 2. Patients were monitored for SBP over two years. TLR2SNPs were identified by hybridization probeassays 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 TLR2Arg753Gln 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 TLR2GT microsatellite polymorphism (OR=3.8, p =0.002) and NOD2variants (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 NOD2risk variants, TLR2polymorphisms indicate increased susceptibility toward SBP in cirrhotic patients with ascites, and the combination of the TLR2GT microsatellite polymorphism with at least one NOD2risk variant enables improved identification of patients with a high risk for SBP.