title: Expression analysis of leukotriene-inflammatory gene interaction network in patients with coronary artery disease.
abstract: OBJECTIVE
  Leukotrienes are important lipid inflammatory mediators that play a pivotal role in the pathogenesis of atherosclerosis. We aimed to construct a network of interactions between leukotrienes and inflammatory biomarkers and evaluate the expression of key members of the leukotriene pathway and leukotriene-induced inflammatory molecules in patients with coronary artery disease (CAD) and healthy controls.
  
  
  METHODS
  Leukotrienes and their regulatory inflammatory molecules reported in the literature were used to construct a biological network employing Gene spring GX v12.5. Key leukotriene genes and their closely interacting members were selected for expression study in 64 patients and 64 matched controls. Four single nucleotide polymorphisms(SNPs) (rs6538697, rs2660898, rs17525495 and rs1978331) in the leukotriene A4 hydrolase(LTA4H) gene were genotyped using SYBR green method, and plasma leukotriene B4 (LTB4) levels were measured using ELISA.
  
  
  RESULTS
  The expression levels of arachidonate 5-lipoxygenase(ALOX5), LTA4H, tumor necrosis factor (TNF) and interleukin-8 (IL-8) genes were significantly higher in patients than in the controls(p＜0.05). IL-8(r=0.35-0.47) and TNF (r=0.42-0.53) expression levels exhibited strong correlations with the leukotriene genes. The SNPs rs17525495 and rs1978331 were associated with LTA4H mRNA expression, while LTA4H and IL-8 levels were associated with CAD. The addition of these two markers to the conventional risk factors improved the c-statistics(area under the receiver operating characteristic(ROC) curve) from 0.75 to 0.93(p＜0.01), with a Net Reclassification Index of 0.45(p＜0.01) and Integrated Discrimination Improvement of 0.26(p＜0.01).
  
  
  CONCLUSIONS
  Leukotrienes and inflammatory genes, in particular, LTA4H and IL-8, exhibit close association in subjects with cardiovascular disease. Assessing these markers may provide incremental value for predicting cardiovascular risk beyond that obtained with classical risk factors.
authors.affiliation: Mary and Garry Weston Functional Genomics Unit, Thrombosis Research Institute.
authors.forename: Jiny
authors.initials: J
authors.lastname: Nair
authors.forename: Jayashree
authors.initials: J
authors.lastname: Shanker
authors.forename: Srikarthika
authors.initials: S
authors.lastname: Jambunathan
authors.forename: Prathima
authors.initials: P
authors.lastname: Arvind
authors.forename: Vijay V
authors.initials: VV
authors.lastname: Kakkar
mesh_terms: D000368:Aged; D000465:Algorithms; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004851:Epoxide Hydrolases / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D007249:Inflammation; D016209:Interleukin-8 / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016209:Interleukin-8; D015289:Leukotrienes; D014409:Tumor Necrosis Factor-alpha; D001094:Arachidonate 5-Lipoxygenase; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase