Promoter methylation in coagulation F7 gene influences plasma FVII concentrations and relates to coronary artery disease.

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.