Abstract | 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.
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Authors | Simonetta Friso, Valentina Lotto, Sang-Woon Choi, Domenico Girelli, Mirko Pinotti, Patrizia Guarini, Silvia Udali, Patrizia Pattini, Francesca Pizzolo, Nicola Martinelli, Roberto Corrocher, Francesco Bernardi, Oliviero Olivieri |
Journal | Journal of medical genetics
(J Med Genet)
Vol. 49
Issue 3
Pg. 192-9
(Mar 2012)
ISSN: 1468-6244 [Electronic] England |
PMID | 22315437
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
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Topics |
- Adult
- Aged
- Biomarkers
(blood)
- Case-Control Studies
- Coronary Artery Disease
(blood, genetics)
- DNA Methylation
- Epigenesis, Genetic
- Factor VII
(genetics, metabolism)
- Female
- Genetic Association Studies
- Haplotypes
- Humans
- Male
- Middle Aged
- Polymorphism, Genetic
- Promoter Regions, Genetic
- Risk Factors
- Sequence Analysis, DNA
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