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

Claudia Bozzini; Domenico Girelli; Francesco Bernardi; Paolo Ferraresi; Oliviero Olivieri; Mirko Pinotti; Nicola Martinelli; Franco Manzato; Simonetta Friso; Giuliano Villa; Francesca Pizzolo; Federico Beltrame; Roberto Corrocher

doi:10.1160/TH04-02-0130

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2004; 92(03): 541-549
DOI: 10.1160/TH04-02-0130

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

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

Claudia Bozzini

¹Department of Clinical and Experimental Medicine, University of Verona

,

Domenico Girelli

¹Department of Clinical and Experimental Medicine, University of Verona

,

Francesco Bernardi

²Department of Biochemistry and Molecular Biology, University of Ferrara

,

Paolo Ferraresi

²Department of Biochemistry and Molecular Biology, University of Ferrara

,

Oliviero Olivieri

¹Department of Clinical and Experimental Medicine, University of Verona

,

Mirko Pinotti

²Department of Biochemistry and Molecular Biology, University of Ferrara

,

Nicola Martinelli

¹Department of Clinical and Experimental Medicine, University of Verona

,

Franco Manzato

³Laboratory of Clinical Pathology, Hospital “Carlo Poma”, Mantova

,

Simonetta Friso

¹Department of Clinical and Experimental Medicine, University of Verona

,

Giuliano Villa

¹Department of Clinical and Experimental Medicine, University of Verona

,

Francesca Pizzolo

¹Department of Clinical and Experimental Medicine, University of Verona

,

Federico Beltrame

⁴Institute of Cardiology, University of Verona, Italy

,

Roberto Corrocher

¹Department of Clinical and Experimental Medicine, University of Verona

› Institutsangaben

Abstract

Summary

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.

Keywords

Factor VII - gene polymorphisms - myocardial infarction

Volltext

Referenzen

References
1 Rao LV, Rapaport SI. Activation of factor VII bound to tissue factor: a key early step in the tissue factor pathway of blood coagulation. Proc Natl Acad Sci USA 1988; 85: 6687-91.
2 Wilcox JN, Smith KM, Schwartz SM. et al. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-43.
3 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242-50.
4 Meade TW, Mellows S, Brozovic M. et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 02: 533-7.
5 Heinrich J, Balleisen L, Schulte H. et al. Fibrinogen and factor VII in the prediction of coronary risk: results from the PROCAM study in healthy men. Arterioscler Thromb 1994; 14: 54-59.
6 Redondo M, Watzke HH, Stucki B. et al. Coagulation factors II, V, VII, and X, prothrombin gene 20210G→A transition, and factor V Leiden in coronary artery disease: high factor V clotting activity is an independent risk factor for myocardial infarction. Arterioscler Thromb Vasc Biol 1999; 19: 1020-5.
7 Noto D, Barbagallo CM, Cefalù AB. et al. Factor VII activity is an independent predictor of cardiovascular mortality in elderly women of a Sicilian population: results of an 11-year follow-up. Thromb Haemost 2002; 87: 206-10.
8 Folsom AR, Wu KK, Rosamond WD. et al. A prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 1997; 96: 1102-8.
9 Smith FB, Lee AJ, Fowkes FGR. et al. Hemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol 1997; 17: 3321-5.
10 Miller GJ, Martin JC, Mitropoulos KA. et al. Activation of factor VII during alimentary lipemia occurs in healthy adults and patients with congenital factor XII or factor XI deficiency, but not in patients with factor IX deficiency. Blood 1996; 87: 4187-96.
11 Simpson HCR, Meade TW, Stirling Y. et al. Hypertriglyceridaemia and hypercoagulability. Lancet 1983; 02: 786-90.
12 Feng D, Tofler GH, Larson MG. et al. Factor VII gene polymorphism, Factor VII levels, and prevalent cardiovascular disease. Arterioscler Thromb Vasc Biol 2000; 20: 593-600.
13 Mariani G, Bernardi F, Bertina R. et al. Serum phospholipids are the main environmental determinants of activated factor VII in the most common FVII genotype. European Union Concerted Action “Clotart”. Haematologica 1999; 84: 620-6.
14 Balleisen L, Bailey J, Epping PH. et al. Epidemiological Study on factor VII, factor VIII and fibrinogen in an industrial population: I. Baseline data on the relation to age, gender, body-weight, smoking, alcohol, pillusing, and menopause. Thromb Haemost 1985; 54: 475-9.
15 Scarabin PY, Vissac AM, Kirzin JM. et al. Population correlates of coagulation factor VII: importance of age, sex, and menopausal status as determinants of activated factor VII. Artherioscler Thromb Vasc Biol 1996; 16: 1170-6.
16 De Lange M, Snieder H, Ariens RA. et al. The genetics of haemostasis: a twin study. Lancet 2001; 357: 101-5.
17 Girelli D, Corrocher R. Polymorphisms in the Factor VII gene and the risk of myocardial infarction. In: Harrison’s Principles of Internal Medicine online. Braunwald E, Fauci AS, Isselbacher KJ, Kasper DL, Hauser SL, Longo DL, Jameson JL. Editors. Editorial Related to Chapter 243 (Acute myocardial infarction) Mc Graw-Hill; 2001
18 Green F, Kelleher C, Wilkes H. et al. A common genetic polymorphism associated with lower coagulation factor VII levels in healthy individuals. Arterioscler Thromb 1991; 11: 540-6.
19 Marchetti G, Patracchini P, Papaschini M. et al. A polymorphism in the 5’ region of coagulation factor VII gene (F7) caused by an inserted decanucleotide. Hum Genet 1993; 90: 575-576.
20 Pollak ES, Hung HL, Godin W. et al. Functional characterization of the human factor VII 5’-flanking region. J Biol Chem 1996; 271: 1738-1747.
21 Bernardi F, Arcieri P, Bertina RM. et al. Contribution of factor VII genotype to activated FVII levels. Differences in genotype frequencies between northern and southern European populations. Arterioscler Thromb Vasc Biol 1997; 17: 2548-2553.
22 Di Castelnuovo A, D’Orazio A, Amore C. et al. Genetic modulation of coagulation factor VII plasma levels: contribution of different polymorphisms and gender-related effects. Thromb Haemost 1998; 80: 592-7.
23 Humphries S, Temple A, Lane A. et al. Low plasma levels of factor VIIc and antigen are more strongly associated with the 10 base pair promoter (-323) insertion than the glutamine 353 variant. Thromb Haemost 1996; 75: 567-72.
24 Iacoviello L, Di Castelnuovo A, De Knijff P. et al. Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction. N Engl J Med 1998; 338: 79-85.
25 Girelli D, Russo C, Ferraresi P. et al. Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease. N Engl J Med 2000; 343: 774-80.
26 Mrozikiewicz PM, Cascorbi I, Ziemer S. et al. Reduced procedural risk for coronary cathether interventions in carriers of the coagulation factor VII-gln gene. J Am Coll Cardiol 2000; 36: 1520-5.
27 Mikkelsson J, Karhunen PJ. Genetic variation in coagulation factors II, V, VII and fatal MI. Thromb Haemost 2002; 87: 349-50.
28 Wu AHB, Tsongalis GJ. Correlation of polymorphisms to coagulation and biochemical risk factors for cardiovascular disease. Am J Cardiol 2001; 87: 1361-66.
29 Lane A, Green F, Scarabin PY. et al. Factor VII Arg/Gln353 polymorphism determines factor VII coagulant activity in patients with myocardial infarction (MI) and control subjects in Belfast and in France but is not a strong indicator of MI risk in the ECTIM study. Atherosclerosis 1996; 119: 119-27.
30 Doggen CJM, Cats VM, Bertina RM. et al. A genetic propensity to high factor VII is not associated with the risk of myocardial infarction in men. Thromb Haemost 1998; 80: 281-5.
31 Atherosclerosis Thrombosis and Vascular Biology Italian Study Group. No evidence of association between prothrombotic gene polymorphisms and the development of acute myocardial infarction at a young age. Circulation 2003; 107: 1117-22.
32 Van’t Hooft FM, Silveira A, Tornvall P. et al. Two common functional polymorphisms in the promoter region of the coagulation factor VII gene determining plasma factor VII activity and mass concentration. Blood 1999; 93: 3432-41.
33 Carew JA, Basso F, Miller GJ. et al. A functional haplotype in the 5’ flanking region of the factor VII gene is associated with an increased risk of coronary heart disease. J Thromb Haemost 2003; 01: 2179-85.
34 Iacoviello L, Donati MB. Interpretation of thrombosis prevention trial. Lancet 1998; 351: 1205.
35 Miller GJ, Stirling Y, Esnouf MP. et al. Factor VII-deficient substrate plasmas depleted of protein C raise the sensitivity of the factor VII bio-assay to activated factor VII: an international study. Thromb Haemost 1994; 71: 38-48.
36 Di Bitondo R, Hall AJ, Peake IR. et al. Oestrogenic repression of human coagulation factor VII expression mediated through an oestrogen response element sequence motif in the promoter region. Hum Mol Genet 2002; 11: 723-31.
37 Gambaro G, Anglani F, D’Angelo A. Association studies of genetic polymorphisms and complex disease. Lancet 2000; 355: 308-11.
38 Grant PJ. The genetics of atherothrombotic disorders: a clinician’s view. J Thromb Haemost 2003; 01: 1381-90.
39 Hurlen M, Abdelnoor M, Smith P. et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 2002; 347: 969-74.
40 Brouwer MA, Verheugt FWA. Oral anticoagulation for acute coronary syndromes. Circulation 2002; 105: 1270-4.
41 Van Es RF, Jonker JJ, Verheught FW. et al. Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2 (ASPECT-2) Research Group. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet 2002; 360: 109-13.