Influence of polymorphisms in the factor VII gene promoter on activated factor VII levels and on the risk of myocardial infarction in advanced coronary atherosclerosis.
In this study, we investigate the influence of three factor VII (FVII) gene polymorphisms on activated FVII levels (FVIIa), and also on the risk of myocardial infarction (MI) in patients with advanced coronary atherosclerotic disease (CAD). The -323A2 allele in the promoter is known to be associated with low FVII levels, and has been suggested to protect against MI in some studies. The -402GA promoter polymorphism, that in vitro has been associated with having opposite effect, is less well studied clinically. For this study, plasma FVIIa levels and three FVII gene polymorphisms were assessed in 934 subjects of both sexes, all with an angiographic documentation of coronary vessels. Our results show that two promoter polymorphisms, plasma cholesterol, and gender, were significant predictors of FVIIa levels. The -402A allele was associated to a significant increase of FVIIa levels in males (by 19.2%). In a selected clinical model including the patients with severe CAD, with or without a thrombotic complication (MI), male carriers of the -402A had an increased risk of MI (OR=1.79; 95% CI 1.15-2.80). The -323A2 allele was associated to a significant decrease in FVIIa (by 36.02% in males, and 39.7% in females). Male carriers of the -323A2 were protected from MI (OR=0.6; 95% CI 0.39-0.94), but only after correction for the confounding effect of combined heterozygosity for the promoter polymorphisms. We can conclude that FVII gene polymorphisms with an opposite effect on FVIIa levels may modulate the risk of MI in males with advanced CAD. This study highlights a "within-gene" interaction, and the need to explore polymorphisms in candidate gene(s) in detail.
Bozzini
Claudia
C
Department of Clinical and Experimental Medicine, University of Verona, Policlinico G.B. Rossi, 37134 Verona, Italy. claudibozz@inwind.it
Girelli
Domenico
D
Bernardi
Francesco
F
Ferraresi
Paolo
P
Olivieri
Oliviero
O
Pinotti
Mirko
M
Martinelli
Nicola
N
Manzato
Franco
F
Friso
Simonetta
S
Villa
Giuliano
G
Pizzolo
Francesca
F
Beltrame
Federico
F
Corrocher
Roberto
R
D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000150:complications* / Q000235:genetics; D005167:Factor VII / Q000235:genetics*; D015942:Factor VIIa / Q000032:analysis* / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000209:etiology* / Q000235:genetics; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012306:Risk; D012737:Sex Factors
D005167:Factor VII; D015942:Factor VIIa