Novel polymorphism of interleukin-18 associated with greater inflammation after cardiac surgery

Introduction: Interleukin (IL)-18 is a key modulator of the cytokine response that leads to organ dysfunction and prolonged intensive care unit (ICU) stay after cardiopulmonary bypass surgery. We hypothesised that variation in the pro-inflammatory gene IL-18 is associated with adverse clinical outcome because of a more intense inflammatory response. Methods: Haplotypes of the IL-18 gene were inferred from genotypes of 23 Coriell Registry subjects. Four haplotype tag single nucleotide polymorphisms (-607 C/A, -137 G/C, 8148 C/T and 9545 T/G) identified four major haplotype clades. These polymorphisms were genotyped in 658 Caucasian patients undergoing cardiopulmonary bypass surgery. Clinical phenotypes were collected by retrospective chart review. Results: Patients homozygous for the T allele of the 9545 T/G polymorphism had an increased occurrence of prolonged ICU stay (6.8% for TT genotype versus 2.7% for GG or GT genotype; p = 0.015). Patients homozygous for the T allele also had increased occurrence of low systemic vascular resistance index (62%) compared with the GG and GT genotypes (53%; p = 0.045). Patients homozygous for the T allele had increased serum IL-18 concentrations 24 hours post-surgery (p = 0.018), increased pro-inflammatory tumour necrosis factor alpha concentrations (p = 0.014) and decreased anti-inflammatory serum IL-10 concentrations (p = 0.018) 24 hours post-surgery. Conclusions: The TT genotype of the IL-18 9545 T/G polymorphism is associated with an increased occurrence of prolonged ICU stay post-surgery and greater post-surgical inflammation. These results may be explained by greater serum IL-18, leading to greater pro-versus anti-inflammatory cytokine expression.Critical Care Medicine, Division ofMedicine, Faculty ofMedicine, Department ofReviewedFacult