Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis

Abstract

This study aims to determine the influence of the polymorphism within the intron 2 of the interleukin-1 receptor antagonist gene (IL-1RN*) on the outcome of severe sepsis, and to assess its functional significance by correlating this polymorphism with the total production of interleukin-1 receptor antagonist (IL-1Ra) protein determined in stimulated peripheral blood mononuclear cells (PBMC). A group of 78 patients with severe sepsis (51 survivors and 27 nonsurvivors) was compared with a healthy control group of 130 blood donors, and 56 patients with uncomplicated pneumonia. We found a significant association between IL-1RN* polymorphism and survival. Thus, after adjusting for age and APACHE II score, multiple logistic regression analysis showed that patients homozygotes for the allele *2 had a 6.47-fold increased risk of death (95% CI 1.01--41.47, P = 0.04). Besides, compared with patients homozygous or heterozygous for the allele *1, IL-1RN*2 homozygotes produced significantly lower levels of IL-1Ra from their PBMC. Our results suggest that insufficient production of this cytokine might contribute, among other factors, to the higher mortality rate found in severe sepsis patients with the IL-1RN*2 homozygous genotype.

Fig. 1

Interleukin-1 receptor antagonist genotypes. (a) Scheme of the IL-1RN* polymorphism; variable number of tandem repeats (VNTR) for each allele are indicated in box. (b) Agarose gel (2%) displaying IL-1RN* genotypes in 19 healthy controls: homozygotes *1/1 (lanes 1, 3, 4, 6 and 9); homozygotes *2/2 (lanes 8, 13 and 18); heterozygotes *1/5 (lane 2); heterozygotes *1/2 (lanes 5, 7, 11, 12, 14, 15, 16 and 17 and 19); heterozygotes *2/5 (lane 10). M = base pair marker.