Smoking, F2RL3 methylation, and prognosis in stable coronary heart disease
Smoking, F2RL3 methylation, and prognosis in stable coronary heart disease
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DOI：
10.1093/eurheartj/ehs091
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发表时间：
2012-11-01
影响因子：
39.3
通讯作者：
Brenner, Hermann
中科院分区：
文献类型：
--
作者：
Breitling, Lutz Philipp;Salzmann, Katrin;Brenner, Hermann
在最近的一项全基因组研究中，发现F2RL3基因中的胞嘧啶碱基在吸烟者中被低甲基化，该基因编码与心血管生理学相关的蛋白质。我们的目的是确定甲基化在F2RL3 locus.In KAROLA前瞻性队列研究的临床意义，1206名参与者的住院心血管康复计划后，经历了急性冠脉综合征，心肌梗死，或冠状动脉介入治疗招募在德国的两个诊所。进行了8年的积极随访。采用Sequenom基质辅助激光解吸电离飞行时间质谱法对F2RL3基因座的甲基化进行了表征。通过多重Cox回归估计混杂因素控制的风险比，研究甲基化和吸烟与继发性心血管事件、病因特异性死亡率和全因死亡率的关系。共观察到49例非致死性心肌梗死、41例非致死性卒中、64例心血管死亡和50例其他原因导致的死亡。在Coxs模型中控制了已建立的预后因素，F2RL3甲基化与死亡率密切相关。与最高四分位数相比，最低四分位数甲基化受试者心血管、非心血管或任何原因死亡的校正风险比（95个置信区间）分别为2.32（0.975.58）、5.16（1.8114.7）和3.19（1.646.21）。相反，未观察到与合并次要事件结局的相关性。当F2RL3被纳入回归模型时，吸烟与所有结局的强相关性明显减弱，结果似乎表明F2RL3甲基化是吸烟有害影响的潜在介导者，并与稳定型冠心病患者的死亡率密切相关。需要多学科的研究努力来揭示这些明显的关联的预后、预防和治疗潜力。
In a recent genome-wide study, cytosine bases in the F2RL3 gene, which codes for a protein relevant for cardiovascular physiology, were discovered to be hypomethylated in smokers. We aimed to determine the clinical importance of methylation at the F2RL3 locus.In the KAROLA prospective cohort study, 1206 participants of inpatient cardiovascular rehabilitation programmes after experiencing an acute coronary syndrome, myocardial infarction, or coronary intervention were recruited in two clinics in Germany. Active follow-up was conducted over 8 years. Methylation at loci in F2RL3 was characterized by Sequenom matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Associations of methylation and smoking with secondary cardiovascular events, and cause-specific and all-cause mortality were examined by multiple Coxs regression estimating confounder-controlled hazard ratios. A total of 49 non-fatal myocardial infarctions, 41 non-fatal strokes, 64 cardiovascular deaths, and 50 deaths due to other causes were observed. In Coxs models controlling for established prognostic factors, F2RL3 methylation was strongly associated with mortality. Adjusted hazard ratios (95 confidence intervals) for death from cardiovascular, non-cardiovascular, or any cause were 2.32 (0.975.58), 5.16 (1.8114.7), and 3.19 (1.646.21) in subjects in the lowest quartile of methylation in comparison to the highest quartile. In contrast, no association was seen with the combined secondary event outcome. The strong association of smoking with all outcomes was markedly attenuated when F2RL3 was included in the regression models.The results seem to indicate methylation in F2RL3 to be a potential mediator of the detrimental impact of smoking and to be strongly related to mortality among patients with stable coronary heart disease. Multidisciplinary research efforts are needed to unravel prognostic, preventive, and therapeutic potentials of these pronounced associations.