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.
- DNA promoter methylation
- coagulation FVII
- F7 polymorphisms
- coronary artery disease
- promoter methylation
- nutrition and metabolism
- cardiovascular medicine
- haematology (coagulation)
- haematology (incl blood transfusion)
- ischaemic heart disease
- venous thromboembolism
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Funding This work was supported by the National Funding of the Ministry of University, Scientific and Technologic Research (Drs Girelli, Olivieri, Corrocher, Friso, Bernardi, Pinotti), and by the Fondazione Cassa di Risparmio di Verona Vicenza Belluno e Ancona, Verona, Italy (Drs Friso and Girelli).
Competing interests None.
Patient consent A detailed informed consent approved by our Institutional review Board has been signed by each participating subject after full explanation of the study.
Ethics approval This study was conducted with the approval of the University Hospital of the University of Verona School of Medicine (Verona, Italy) Ethical Committee and the Ethical Review Board of the University Hospital of Verona.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement At the present moment we would not place the dataset in open repositories.
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