The association of interleukin 6 haplotype clades with mortality in critically ill adults.

BACKGROUND Interleukin 6 (IL-6) is a key proinflammatory cytokine in the systemic inflammatory response syndrome (SIRS). A G-->C polymorphism at position -174 of the IL-6 gene is associated with an adverse outcome in a number of inflammatory diseases, although its association with sepsis as an outcome remains unclear. We tested the hypothesis that specific haplotype clades of IL-6 may be associated with an outcome of SIRS. METHODS We studied a cohort of 228 critically ill white patients who met at least 2 of 4 SIRS criteria. Clinical data were collected over 28 days after hospital admission. Haplotypes of IL-6 were inferred from publicly available data using PHASE (software for haplotype reconstruction and recombination rate estimation from population data), and cladistic structure was determined using Molecular Evolutionary Genetic Analyses (MEGA2) software. Then, a minimum set of "haplotype tag" single nucleotide polymorphisms (-174G/C, 1753C/G, and 2954G/C) that defined all 4 major haplotype clades of the IL-6 gene was chosen for further genotyping. RESULTS Patients who had 2 copies of haplotypes from within the haplotype clades -174C/1753C/2954G (C/C/G), G/G/G, or G/C/C had a greater 28-day mortality compared with patients who carried 1 or no copies of these haplotypes (40.0% vs 26.0%; P = .02). These patients also had fewer days alive and free of multiple system organ dysfunction (P<.05). There were no associations between individual single nucleotide polymorphisms (including -174G/C) and survival or organ dysfunction. CONCLUSIONS The C/C/G, G/G/G, and G/C/C haplotype clades of IL-6 were strongly associated with increased mortality and more organ dysfunction in a cohort of critically ill patients who had SIRS. Haplotype-based analysis succeeded in identifying this association, whereas individual single nucleotide polymorphism-based analysis failed.