Nair Jiny, Shanker Jayashree, Jambunathan Srikarthika, Arvind Prathima, Kakkar Vijay V
Mary and Garry Weston Functional Genomics Unit, Thrombosis Research Institute.
J Atheroscler Thromb. 2014;21(4):329-45. doi: 10.5551/jat.20123. Epub 2013 Dec 20.
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.
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.
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).
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.
白三烯是重要的脂质炎症介质，在动脉粥样硬化的发病机制中起关键作用。我们旨在构建白三烯与炎症生物标志物之间的相互作用网络，并评估冠状动脉疾病（CAD）患者和健康对照中白三烯途径关键成员及白三烯诱导的炎症分子的表达。
利用文献中报道的白三烯及其调节性炎症分子，采用Gene spring GX v12.5构建生物网络。选择关键的白三烯基因及其密切相互作用的成员，在64例患者和64例匹配对照中进行表达研究。采用SYBR Green法对白三烯A4水解酶（LTA4H）基因中的4个单核苷酸多态性（SNP）（rs6538697、rs2660898、rs17525495和rs1978331）进行基因分型，并用ELISA法检测血浆白三烯B4（LTB4）水平。
花生四烯酸5-脂氧合酶（ALOX5）、LTA4H、肿瘤坏死因子（TNF）和白细胞介素-8（IL-8）基因的表达水平在患者中显著高于对照组（p＜0.05）。IL-8（r=0.35 - 0.47）和TNF（r=0.42 - 0.53）的表达水平与白三烯基因呈强相关性。SNP rs17525495和rs1978331与LTA4H mRNA表达相关，而LTA4H和IL-8水平与CAD相关。将这两个标志物添加到传统危险因素中，使c统计量（受试者工作特征曲线下面积）从0.75提高到0.93（p＜0.01），净重新分类指数为0.45（p＜0.01），综合判别改善为0.26（p＜0.01）。
白三烯与炎症基因，特别是LTA4H和IL-8，在心血管疾病患者中表现出密切关联。评估这些标志物可能为预测心血管风险提供超出经典危险因素的额外价值。
