Novel polymorphism of interleukin-18 associated with greater inflammation after cardiac surgery.
BACKGROUND
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.
Shaw
David M
DM
Critical Care Research Laboratories, Heart + Lung Institute, University of British Columbia, Vancouver, BC, Canada.
Sutherland
Ainsley M
AM
Russell
James A
JA
Lichtenstein
Samuel V
SV
Walley
Keith R
KR
D000368:Aged; D006348:Cardiac Surgical Procedures / Q000009:adverse effects*; D015331:Cohort Studies; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000502:physiology*; D020382:Interleukin-18 / Q000097:blood / Q000235:genetics* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011183:Postoperative Complications / Q000097:blood / Q000209:etiology; D012042:Registries; D012189:Retrospective Studies; D014655:Vascular Resistance / Q000235:genetics; D014657:Vasculitis / Q000097:blood / Q000209:etiology / Q000235:genetics*
D018836:Inflammation Mediators; D020382:Interleukin-18