Abstract
Alterations of the innate immunity contribute to the development of spontaneous bacterial peritonitis (SBP) in liver cirrhosis. Given its role in immune signaling, antimicrobial function, and macrophage differentiation, we hypothesized that genetic polymorphisms of TRAF6 modulate the risk of SBP. Thus, we determined theTRAF6 haplotype in 432 patients with cirrhosis and ascites using the haplotype-tagging single nucleotide polymorphisms rs331457 and rs5030419. In addition, peritoneal macrophages were immunomagnetically isolated and characterized. Overall, 122 (28%) patients had an episode of SBP. In the combined prospective-retrospective analysis the frequency of SBP differed between the four haplotypes (P = 0.014) and was the highest in 102 patients carrying the rs331457 but not the rs5030419 variant, when compared to other haplotypes (odds ratio 1.95 [1.22–3.12]) or to the wild-type (odds ratio 1.71 [1.04–2.82]). This association was confirmed in multivariate logistic regression (adjusted odds ratio 2.00 [1.24–3.22]) and in prospective sensitivity analysis (hazard ratio 2.09 [1.08–4.07]; P = 0.03). The risk haplotype was associated with lower concentrations of the immune activation marker soluble CD87 in ascitic fluid and with a decreased expression of IL-6 and CXCL8 in isolated peritoneal macrophages. In conclusion, genetic polymorphisms of TRAF6 are associated with decreased peritoneal immune activation and an increased risk of SBP.
Highlights
Spontaneous bacterial peritonitis (SBP) is a frequent infectious complication in decompensated cirrhosis, which occurs in approximately 25% of patients and is associated with significant mortality[1, 2]
Owing to its nodal bottleneck position in pattern recognition receptors (PRR) signaling and its importance in immune activation[17] (Fig. 1A), we hypothesized a role of germ line polymorphisms of Tumor-necrosis factor receptor-associated factor 6 (TRAF6) gene for peritoneal immunity and the development of spontaneous bacterial peritonitis (SBP)
We evaluated this hypothesis in a large German cohort of hospitalized patients with decompensated cirrhosis and ascites
Summary
Spontaneous bacterial peritonitis (SBP) is a frequent infectious complication in decompensated cirrhosis, which occurs in approximately 25% of patients and is associated with significant mortality[1, 2]. Multiple lines of evidence link alterations of the innate immunity on the gut mucosal, peritoneal, or systemic level with the risk of SBP In this context, monocytes and macrophages are crucial for pathogen recognition and bacterial clearance as they express a variety of extraand intracellular pattern recognition receptors (PRR) to recognize conserved pathogen-associated molecular patterns (PAMPs). Owing to its nodal bottleneck position in PRR signaling and its importance in immune activation[17] (Fig. 1A), we hypothesized a role of germ line polymorphisms of TRAF6 gene for peritoneal immunity and the development of SBP We evaluated this hypothesis in a large German cohort of hospitalized patients with decompensated cirrhosis and ascites
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