title: Circulating levels of IL-18 are significantly influenced by the IL-18 +183 A/G polymorphism in coronary artery disease patients with diabetes type 2 and the metabolic syndrome: an observational study.
abstract: BACKGROUND
  Increased IL-18 serum levels have been associated with diabetes type 2, metabolic syndrome and the severity of atherosclerosis. The present study investigated the presence and influence of IL-18 genetic variants on gene- and protein expression in stable coronary artery disease (CAD) patients.
  
  
  METHODS
  The +183 A/G (rs 5744292), -137 G/C (rs 187238) and -607 C/A (rs 1946518) polymorphisms were determined in 1001 patients with angiographically verified stable CAD, and in 204 healthy controls. IL-18 gene-expression was measured in circulating leukocytes in 240 randomly selected patients. Circulating IL-18 and IL-18 binding protein levels were measured immunologically in all patients.
  
  
  RESULTS
  The +183 G-allele associated significantly with lower serum levels of IL-18 (p = 0.002, adjusted for age, glucose, body mass index and gender) and a 1.13- fold higher IL-18 gene-expression (p = 0.010). No influence was observed for the -137 G/C and -607 C/A polymorphisms. The IL-18 binding protein levels were not influenced by IL-18 genotypes. IL-18 levels were significantly higher in men as compared to women, and in patients with diabetes type 2 and metabolic syndrome compared to those without (p ≤ 0.001, all). The reduction in IL-18 levels according to the +183 G-allele was 3-4 fold more pronounced in diabetes and metabolic syndrome as compared to unaffected patients.Finally, the +183 AA genotype was more frequent in patients with hypertension (p = 0.042, adjusted for age, body mass index and gender).
  
  
  CONCLUSIONS
  The reduction in serum IL-18 levels across increasing numbers of +183 G-alleles was especially apparent in patient with diabetes type 2 and metabolic syndrome, suggesting a beneficial GG genotype in relation to cardiovascular outcome in these patients.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT00222261.
authors.affiliation: Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital, Ulleval, Norway. trineoa@medisin.uio.no
authors.forename: Trine B
authors.initials: TB
authors.lastname: Opstad
authors.forename: Alf Å
authors.initials: AÅ
authors.lastname: Pettersen
authors.forename: Harald
authors.initials: H
authors.lastname: Arnesen
authors.forename: Ingebjørg
authors.initials: I
authors.lastname: Seljeflot
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000097:blood* / Q000150:complications / Q000235:genetics*; D048909:Diabetes Complications / Q000097:blood / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D020382:Interleukin-18 / Q000097:blood* / Q000235:genetics*; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood* / Q000150:complications / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D012333:RNA, Messenger; C118370:interleukin-18 binding protein