[Genomic polymorphism within interleukin-1 family cytokines influences the outcome of septic patients]

Abstract

Objective: To determine the allele frequencies and genotype distribution of interleukin (IL)-1 alpha, IL-1 beta and IL-1 receptor antagonist (IL-1ra) gene polymorphism in septic patients.

Methods: A prospective, consecutive entry study was made among 60 patients with the diagnosis of sepsis who were admitted consecutively into the general intensive care unit (ICU), Peking Union Medical College Hospital between 1997 and 1999. APACHE II scoring and MODS scoring were made within 24 hours after admission. The genomic DNA of peripheral blood nucleated cells was extracted. The polymorphic regions within intron 6 of IL-1 alpha gene containing variable numbers of a tandem repeat (VNTR) of 46 bp, and intron 2 of IL-1ra gene containing VNTR of 86 bp were amplified by means of polymerase chain reaction (PCR). Alleles A1-4 and RN1-4 were identified according to the size of amplified DNA product. The region containing the AvaI polymorphic site at position -511 of IL-1 beta gene was amplified by PCR, and subsequently digested with AvaI restriction enzyme.

Results: The frequencies of allele IL-1ra RN2 and genotype RN2/2 in the 60 septic patients were significantly higher than those in normal controls (0.34 vs 0.23, P < 0.01, and 0.12 vs 0.05, P < 0.05, respectively). The allele frequencies or genotype distribution of IL-1 alpha VNTR gene polymorphism and IL-1 beta AvaI polymorphism did not differ between the septic patients and normal controls. In addition, genotypes A2/2, B2/2 and RN2/2 were associated with a significantly higher mortality (80%, 81% and 71%, respectively) in septic patients. Patients with any 2 of the three alleles, i.e. A2, B2 and RN2, suffered from a much more severe sepsis (as measured by APACHE II and MODS scores) and higher mortality rate ( 55-65%), while septic patients with genotypes A1/1, B1/1 or RN1/1 showed a much lower mortality (0-13%).

Conclusion: Allele IL-1RN2 polymorphism, but not IL-1A or IL-1B gene polymorphism, is associated with susceptibility to sepsis. Alleles A2, B2 and RN2 might be important high-risk genetic markers for sepsis.