Effect of the interleukin-6 promoter polymorphism (-174 G/C) on the incidence and outcome of sepsis

Objective: A biallelic polymorphism within the human interleukin (IL)-6 gene promoter region (-174 G/C) has been shown to affect IL-6 transcription in vitro and IL-6 plasma levels in healthy adults. Because IL-6 is excessively released into the circulation during sepsis and closely correlates with the clinical course, we studied whether this promoter polymorphism has an effect on the incidence and/or outcome of sepsis. Design: Population-based association study in critically ill patients and healthy controls. Setting: Surgical intensive care unit (ICU) in a German university hospital. Patients: Surgical patients (n = 326) of German Caucasian origin with an ICU stay of at least 3 days admitted between 1997 and 1999 were prospectively enrolled. In a subset of 50 patients, sepsis was diagnosed according to consensus criteria (American College of Chest Physicians 1992). Healthy sex-matched adults of the same ethnic and geographic background served as controls. Interventions: Blood sampling. Measurements and Main Results: The (-174 G/C) polymorphism was genotyped by an allele-specific polymerase chain reaction. IL-6 plasma levels were determined by enzyme-linked immunosorbent assay. Genotype distribution and allele frequencies did not differ significantly between patients with or without sepsis and healthy controls. In patients who finally succumbed to sepsis, significantly less GG homozygotes were observed compared with survivors (p = .008). Median systemic IL-6 levels in septic patients closely correlated with outcome (p < .0001) but were not associated with the IL-6 promoter genotype, Conclusions: The IL-6 promoter polymorphism (-174 G/C) does not affect the incidence of sepsis. However, the GG homozygous genotype is significantly associated with an improved survival in sepsis. Because this association is independent from the systemic IL-6 response, we suggest that other genetically linked polymorphisms may be the primary cause.