Promoter methylation in coagulation F7 gene influences plasma FVII concentrations and relates to coronary artery disease
Promoter methylation in coagulation F7 gene influences plasma FVII concentrations and relates to coronary artery disease
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DOI：
10.1136/jmedgenet-2011-100195
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发表时间：
2012-03-01
影响因子：
4
通讯作者：
Olivieri, Oliviero
中科院分区：
文献类型：
--
作者：
Friso, Simonetta;Lotto, Valentina;Olivieri, Oliviero
血浆因子VII浓度（FVIIa）是冠状动脉疾病（CAD）风险的标志物，受启动子位点遗传标志物的影响：A2等位基因，由于在位置-323插入10 bp，是较低FVIIa浓度和降低CAD风险的决定因素，而-402A等位基因，由于G>A置换，赋予体外转录活性增加，导致FVIIa更高。然而，表观遗传特征对F7的转录调控，未知的是，目的探讨F7基因启动子区的表观遗传调控及其与F7基因功能多态性的关系。方法与结果F7基因启动子区甲基化及其与F7基因启动子多态性在FVIIa和CAD中的关系通过甲基特异性PCR和亚硫酸氢盐测序技术对253名受试者进行风险评估，其中168名患有CAD，88名无CAD。血浆FVIIa与A1 A1和-402GG的甲基化呈负相关，即不存在罕见的A2和-402A等位基因。与A2 A2相比，FVIIa越高，A1 A1的甲基化越低（p=0.035），而甲基化的变化与不同的-402G>A基因型无关。仅在A1 A1中观察到甲基化诱导的FVIIa浓度的调节，其中与CAD组相比，无CAD组中普遍存在导致较低FVIIa的较高甲基化（p=0.011）。
Background Plasma factor VII concentrations (FVIIa), a marker of coronary artery disease (CAD) risk, are influenced by genetic markers at the promoter site: the A2 allele, due to a 10bp insertion at position -323, is a determinant of lower FVIIa concentrations and reduced CAD risk, while the -402A allele, due to a G>A substitution, confers increased transcriptional activity in vitro resulting in higher FVIIa. Transcriptional regulation of F7 by epigenetic features is, however, still unknown as is the inter-relationship of genetic and epigenetic modifications at the promoter site.Objective To investigate a possible epigenetic regulation of the F7 gene at the promoter region and its link with functional F7 polymorphisms at the same site.Methods and results F7 promoter methylation and its relation to F7 promoter polymorphisms in modulating FVIIa and CAD risk were evaluated by methyl-specific PCR and bisulfite sequencing techniques in 253 subjects, of whom 168 had CAD and 88 were CAD-free. Plasma FVIIa was inversely related to methylation in A1A1 and -402GG, that is in the absence of the rare A2 and -402A allele. The higher FVIIa paralleled the lower methylation in A1A1 compared to A2A2 (p=0.035), while no variation in methylation was associated with the different -402G>A genotypes. The modulation of methylation-induced FVIIa concentrations was observed only in A1A1 where the higher methylation resulting in lower FVIIa was prevalent within the CAD-free group compared to the CAD group (p=0.011).Conclusions Epigenetic regulation through methylation of F7 promoter is associated with CAD by affecting plasma FVIIa concentrations in A1A1 genotypes.