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.


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.
Department of Medicine, University of Verona School of Medicine, Verona, Italy. simonetta.friso@univr.it
Simonetta
S
Friso
Valentina
V
Lotto
Sang-Woon
SW
Choi
Domenico
D
Girelli
Mirko
M
Pinotti
Patrizia
P
Guarini
Silvia
S
Udali
Patrizia
P
Pattini
Francesca
F
Pizzolo
Nicola
N
Martinelli
Roberto
R
Corrocher
Francesco
F
Bernardi
Oliviero
O
Olivieri
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005167:Factor VII / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D017422:Sequence Analysis, DNA
D015415:Biomarkers; D005167:Factor VII