title: Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a).
abstract: OBJECTIVE
  The aim of this study was to assess the influence of pro-inflammatory interleukin (IL)-1 genotype status on the risk for coronary artery disease (CAD), defined as >50% diameter stenosis, and cardiovascular events mediated by oxidized phospholipids (OxPLs) and lipoprotein (Lp) (a).
  
  
  BACKGROUND
  OxPLs are pro-inflammatory, circulate on Lp(a), and mediate CAD. Genetic variations in the IL-1 region are associated with increased inflammatory mediators.
  
  
  METHODS
  IL-1 genotypes, OxPL on apolipoprotein B-100 (OxPL/apoB), and Lp(a) levels were measured in 499 patients undergoing coronary angiography. The composite genotype termed IL-1(+) was defined by 3 single-nucleotide polymorphisms in the IL-1 gene cluster associated with higher levels of pro-inflammatory cytokines. All other IL-1 genotypes were termed IL-1(-).
  
  
  RESULTS
  Among IL-1(+) patients, the highest quartile of OxPL/apoB was significantly associated with a higher risk for CAD compared with the lowest quartile (odds ratio [OR]: 2.84; p = 0.001). This effect was accentuated in patients age ≤60 years (OR: 7.03; p < 0.001). In IL-1(-) patients, OxPL/apoB levels showed no association with CAD. The interaction was significant for OxPL/apoB (OR: 1.99; p = 0.004) and Lp(a) (OR: 1.96; p < 0.001) in the IL-1(+) group versus the IL-1(-) group in patients age ≤60 years but not in those age >60 years. In IL-1(+) patients age ≤60 years, after adjustment for established risk factors, high-sensitivity C-reactive protein, and Lp(a), OxPL/apoB remained an independent predictor of CAD. IL-1(+) patients above the median OxPL/apoB presented to the cardiac catheterization laboratory a mean of 3.9 years earlier (p = 0.002) and had worse 4-year event-free survival (death, myocardial infarction, stroke, and need for revascularization) compared with other groups (p = 0.006).
  
  
  CONCLUSIONS
  Our study suggests that IL-1 genotype status can stratify population risk for CAD and cardiovascular events mediated by OxPL. These data suggest a clinically relevant biological link between pro-inflammatory IL-1 genotype, oxidation of phospholipids, Lp(a), and genetic predisposition to CAD and cardiovascular events.
authors: Division of Cardiovascular Diseases, University of California San Diego, La Jolla, California. Electronic address: stsimikas@ucsd.edu.
authors: Sotirios
authors: S
authors: Tsimikas
authors: Division of Genomic Medicine, University of Sheffield, Sheffield, United Kingdom.
authors: Gordon W
authors: GW
authors: Duff
authors: Department of Cardiology, Geisinger Health System, Danville, Pennsylvania.
authors: Peter B
authors: PB
authors: Berger
authors: Interleukin Genetics, Inc., Waltham, Massachusetts.
authors: John
authors: J
authors: Rogus
authors: Interleukin Genetics, Inc., Waltham, Massachusetts.
authors: Kenneth
authors: K
authors: Huttner
authors: Veterans Affairs Medical Center, San Diego, California.
authors: Paul
authors: P
authors: Clopton
authors: Veterans Affairs North Texas Healthcare System, Dallas, Texas.
authors: Emmanuel
authors: E
authors: Brilakis
authors: Interleukin Genetics, Inc., Waltham, Massachusetts.
authors: Kenneth S
authors: KS
authors: Kornman
authors: Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, California.
authors: Joseph L
authors: JL
authors: Witztum
mesh_terms: D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D015994:Incidence; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D017270:Lipoprotein(a) / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D014481:United States / Q000453:epidemiology
chemical_list: D007375:Interleukin-1; D017270:Lipoprotein(a); D010743:Phospholipids; D004247:DNA
keywords: IL-1; atherosclerosis; genetic risk stratification; haplotype; inflammation; lipoprotein(a); lipoproteins; oxidation; oxidized phospholipids; polymorphism