Wingrove James A, Fitch Karen, Rhees Brian, Rosenberg Steven, Voora Deepak
CardioDx, Inc, 600 Saginaw Dr., Redwood City, CA, 94063, USA.
Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, 101 Science Drive, 2187 CIEMAS, Durham, NC, 27708, UK.
BMC Med Genomics. 2018 Jan 12;11(1):1. doi: 10.1186/s12920-017-0318-6.
Cardiovascular disease and its sequelae are major causes of global mortality, and better methods are needed to identify patients at risk for future cardiovascular events. Gene expression analysis can inform on the molecular underpinnings of risk factors for cardiovascular events. Smoking and aspirin have known opposing effects on platelet reactivity and MACE, however their effects on each other and on MACE are not well described.
We measured peripheral blood gene expression levels of ITGA2B, which is upregulated by aspirin and correlates with platelet reactivity on aspirin, and a 5 gene validated smoking gene expression score (sGES) where higher expression correlates with smoking status, in participants from the previously reported PREDICT trial (NCT 00500617). The primary outcome was a composite of death, myocardial infarction, and stroke/TIA (MACE). We tested whether selected genes were associated with MACE risk using logistic regression.
Gene expression levels were determined in 1581 subjects (50.5% female, mean age 60.66 +/-11.46, 18% self-reported smokers); 3.5% of subjects experienced MACE over 12 months follow-up. Elevated sGES and ITGA2B expression were each associated with MACE (odds ratios [OR] =1.16 [95% CI 1.10-1.31] and 1.42 [95% CI 1.00-1.97], respectively; p < 0.05). ITGA2B expression was inversely associated with self-reported smoking status and the sGES (p < 0.001). A logistic regression model combining sGES and ITGA2B showed better performance (AIC = 474.9) in classifying MACE subjects than either alone (AIC = 479.1, 478.2 respectively).
Gene expression levels associated with smoking and aspirin are independently predictive of an increased risk of cardiovascular events.
心血管疾病及其后遗症是全球死亡的主要原因，需要更好的方法来识别未来有心血管事件风险的患者。基因表达分析可以揭示心血管事件危险因素的分子基础。吸烟和阿司匹林对血小板反应性和主要不良心血管事件（MACE）有已知的相反作用，然而它们对彼此以及对MACE的影响尚未得到充分描述。
我们在先前报道的PREDICT试验（NCT 00500617）的参与者中，测量了整合素α2β3（ITGA2B）的外周血基因表达水平，ITGA2B受阿司匹林上调且与服用阿司匹林时的血小板反应性相关，还测量了一个经过验证的5基因吸烟基因表达评分（sGES），其中较高的表达与吸烟状态相关。主要结局是死亡、心肌梗死和中风/短暂性脑缺血发作（TIA）的复合结局（MACE）。我们使用逻辑回归测试选定基因是否与MACE风险相关。
在1581名受试者（50.5%为女性，平均年龄60.66±11.46岁，18%自我报告为吸烟者）中测定了基因表达水平；3.5%的受试者在12个月随访期间发生了MACE。sGES升高和ITGA2B表达升高均与MACE相关（比值比[OR]分别为1.16[95%置信区间1.10 - 1.31]和1.42[95%置信区间1.00 - 1.97]；p<0.05）。ITGA2B表达与自我报告的吸烟状态和sGES呈负相关（p<0.001）。一个结合sGES和ITGA2B的逻辑回归模型在对MACE受试者进行分类时，表现优于单独使用sGES或ITGA2B（AIC分别为474.9、479.1和478.2）。
与吸烟和阿司匹林相关的基因表达水平可独立预测心血管事件风险增加。
