Department of Medicine, University of Verona School of Medicine, Verona, Italy.
J Med Genet. 2012 Mar;49(3):192-9. doi: 10.1136/jmedgenet-2011-100195. Epub 2012 Feb 7.
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.
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.
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).
Epigenetic regulation through methylation of F7 promoter is associated with CAD by affecting plasma FVIIa concentrations in A1A1 genotypes.
血浆因子 VII 浓度（FVIIa）是冠心病（CAD）风险的标志物，受启动子部位遗传标记的影响：A2 等位基因由于在位置 -323 处插入 10bp，是 FVIIa 浓度降低和 CAD 风险降低的决定因素，而-402A 等位基因由于 G>A 取代，导致体外转录活性增加，从而导致 FVIIa 升高。然而，F7 的转录调控通过表观遗传特征仍然未知，启动子部位的遗传和表观遗传修饰之间的相互关系也是如此。
研究 F7 基因启动子区域可能的表观遗传调控及其与同一区域功能性 F7 多态性的关系。
通过甲基特异性 PCR 和亚硫酸氢盐测序技术，在 253 名受试者中评估了 F7 启动子甲基化及其与调节 FVIIa 和 CAD 风险的 F7 启动子多态性的关系，其中 168 名患有 CAD，88 名无 CAD。血浆 FVIIa 与 A1A1 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 A2A2 相比，A1A1 中的 FVIIa 更高，与之对应的甲基化程度更低（p=0.035），而不同的-402G>A 基因型与甲基化无差异。仅在 A1A1 中观察到甲基化诱导的 FVIIa 浓度的调节，在无 CAD 组中，与 CAD 组相比，导致 FVIIa 降低的更高甲基化更为普遍（p=0.011）。
通过 F7 启动子的甲基化进行表观遗传调控与 CAD 相关，通过影响 A1A1 基因型中的血浆 FVIIa 浓度。
