Evaluation of variation in the antimicrobial peptide beta-defensin 1 as genetic risk factor for spontaneous bacterial peritonitis in patients with advanced cirrhosis

Abstract

Introduction: Bacterial translocation has been associated with the occurrence of spontaneous bacterial peritonitis (SBP) in patients with liver cirrhosis. Recently we and others have shown that genetic variation in the muramyl dipeptide responsive NOD2 gene, which encodes a pivotal guardian of the immunological integrity of barrier organs, is associated with SBP occurrence and mortality of patients with cirrhosis (Hepatology 2010;51:1327 – 33). Human defensins are additional critical factors that promote antimicrobial host response (Hepatology 2012;55:1154 – 63). Therefore we now assessed genetic variation in the human beta-defensin 1 gene (DEFB1) for association with SBP and mortality in the same cohort of patients with cirrhosis. Methods: Three common single nucleotide variants (G-20A/rs11362, C-44G/rs1800972, and G-52A/rs1799946) in the DEFB1 gene that have recently been studied in Crohn disease as well as other acute and chronic inflammatory diseases (PLoS One 2012;e32215) were genotyped in our cohort of patients with advanced cirrhosis. Patients were followed-up for survival and the occurrence of SBP. We tested for genetic associations with the occurrence of SBP in contigency tables and employed log rank statistics to assess the influence of survival. Results: We recruited and genotyped 150 patients with advanced cirrhosis (93% Child B/C). Men were overrepresented in the cohort (72%). Most patients (63%) suffered from alcoholic cirrhosis. Overall, 20 patients developed SBP, and 53 patients died during follow-up. Median survival of the entire cohort was 326 days. None of the DEFB1 SNPs was significantly associated with the occurrence of SBP (all comparisons p > 0.05). Although we observed a better median survival of heterozygous carriers at the rs11362 variant (481 days) as compared to the other genotypes (180 to 240 days, respectively), this trend was not significant. Conclusions: In this cohort of cirrhotic patients an effect of common variation in the beta-defensin 1 gene is unlikely to contribute to the genetic risk. Although bacterial translocation appears to be critical for the development of SBP, thereby affecting survival in patients with advanced cirrhosis, the genetic risk appears to be predominantly conferred by intracellular defence pathways.