Innate Immunity Genes Influence the Severity of Acute Appendicitis

Abstract

In Brief Objective: Using acute appendicitis as a model, we tested the hypothesis that polymorphisms in genes involved in host defense can be associated with the severity of local infection-inflammation in humans. Summary Background Data: Innate immunity is the body's front-line system for antimicrobial host defense. Local inflammation is a major innate immune mechanism for containing and destroying microbes, but it may also contribute to tissue injury. Methods: We studied 134 patients with acute appendicitis treated at an urban hospital. We looked for associations between the severity of appendicitis (uncomplicated vs. perforated or gangrenous), plasma and peritoneal cytokine concentrations, and single nucleotide polymorphisms in genes involved in recognizing bacterial molecules [CD14 (−159 C→T); TLR4 (896 A→G)] and in mounting an inflammatory response [IL-6 (−174 G→C), TNF-α (−308 G→A), IL-1β (−31 C → T)]. Results: Ninety-one patients (68%) had uncomplicated appendicitis and 43 (32%) had complicated disease. The SNPs in the CD14, TLR4, IL-1β, and TNF-α genes were not associated with the severity of appendicitis. A strong association was found between C-allele carriage at −174 in the IL-6 gene and decreased risk of complicated disease (adjusted odds ratio = 0.24, 95% CI = 0.07–0.76). Lower plasma and peritoneal fluid IL-6 concentrations in the IL-6 −174 C-carriers than in the GG homozygotes suggest that this polymorphism contributes to decreased IL-6 production in vivo. Conclusions: Polymorphism in the IL-6 gene was associated with the severity of appendicitis, even after adjustment for duration of symptoms. The risk for developing appendiceal perforation or gangrene may be determined, in part, by variation in the IL-6 gene. To study the influence of genetic polymorphism on the severity of local infection-inflammation in humans, we obtained plasma, peritoneal fluid, and DNA from patients with acute appendicitis. We found that the G→C transition at −174 in the interleukin-6 promoter was associated both with the pathologic severity of appendicitis and with regional and systemic interleukin-6 concentrations. Our findings suggest that the severity of acute appendicitis is influenced, at least in part, by genetic differences in the innate immune response.