title: IL18 haplotypes are associated with serum IL-18 concentrations in a population-based study and a cohort of individuals with premature coronary heart disease.
abstract: BACKGROUND
  Interleukin (IL)-18 is a proinflammatory cytokine that has been implicated in several diseases, including atherosclerosis, and increased circulating IL-18 concentrations increase risk of future coronary heart disease (CHD). We evaluated the effect of common variation within the IL18 gene on concentrations of circulating IL-18.
  
  
  METHODS
  We measured IL-18, by ELISA, in the population-based study group [Carotid Ultrasound Disease Assessment Study (CUDAS)] and a predominantly male cohort with premature cardiovascular disease [Carotid Ultrasound in Patients with Ischaemic Heart Disease (CUPID)]. Using a tagging single-nucleotide polymorphism (SNP) approach that captured >90% of genetic variation, we identified 4 common (>10%) haplotypes.
  
  
  RESULTS
  A common SNP was associated with differences in IL-18 concentrations; in CUDAS individuals carrying 2 copies of the rare allele, concentrations were 13% higher than in those with no copies (P = 0.002). Haplotypes were also associated with significant differences in IL-18 concentrations in CUDAS and CUPID. Haplotype GTATA (frequency 23%) was associated with significantly lower IL-18 than others. In CUDAS, those carrying 2 copies had IL-18 concentrations 15% lower than those carrying no copies (P = 0.002); in CUPID, the difference was 22% (P = 0.004). These associations remained significant after adjustment for age, sex, hypertension, HDL cholesterol, waist-to-hip ratio, and alcohol consumption. Despite being associated with differences in IL-18 concentrations, the haplotypes did not occur at different frequencies in those with or without carotid atherosclerotic plaques.
  
  
  CONCLUSIONS
  Variation within IL18 affects IL-18 concentrations in healthy and diseased individuals and thus may influence the pathophysiology of plaques at all stages of CHD progression.
authors.affiliation: Department of Cardiovascular Genetics, University College London, London, United Kingdom.
authors.forename: Simon R
authors.initials: SR
authors.lastname: Thompson
authors.forename: Pamela A
authors.initials: PA
authors.lastname: McCaskie
authors.forename: John P
authors.initials: JP
authors.lastname: Beilby
authors.forename: Joseph
authors.initials: J
authors.lastname: Hung
authors.forename: Michelle
authors.initials: M
authors.lastname: Jennens
authors.forename: Caroline
authors.initials: C
authors.lastname: Chapman
authors.forename: Peter
authors.initials: P
authors.lastname: Thompson
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D015331:Cohort Studies; D003327:Coronary Disease / Q000097:blood*; D003430:Cross-Sectional Studies; D005260:Female; D006239:Haplotypes; D006801:Humans; D020382:Interleukin-18 / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D020382:Interleukin-18