Fibrinogen, Factor VII and PAI-1 Genotypes and the Risk of Coronary and Peripheral Atherosclerosis: Edinburgh Artery Study

A. J. Lee; F. G. R. Fowkes; G. D. O. Lowe; J. M. Connor; A. Rumley

doi:10.1055/s-0037-1614523

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1999; 81(04): 553-560
DOI: 10.1055/s-0037-1614523

Rapid Communication

Schattauer GmbH

Fibrinogen, Factor VII and PAI-1 Genotypes and the Risk of Coronary and Peripheral Atherosclerosis: Edinburgh Artery Study

A. J. Lee

²Institute of Medical Genetics, Yorkhill Hospitals Campus, Glasgow, UK

,

F. G. R. Fowkes

²Institute of Medical Genetics, Yorkhill Hospitals Campus, Glasgow, UK

,

G. D. O. Lowe

¹Haemostasis, Thrombosis and Vascular Medicine Unit, University Department of Medicine, Glasgow

,

J. M. Connor

²Institute of Medical Genetics, Yorkhill Hospitals Campus, Glasgow, UK

,

A. Rumley

¹Haemostasis, Thrombosis and Vascular Medicine Unit, University Department of Medicine, Glasgow

› Author Affiliations

Abstract

Summary

There are now many epidemiological studies that have shown a relationship between haemostatic factors and subsequent risk of both coronary and peripheral arterial disease. However, there is less information on the association between genetic variation in these factors and the risks of coronary and peripheral arterial disease. As part of the five-year follow-up of the Edinburgh Artery Study, polymorphisms of the fibrinogen (-455G/A), factor VII (R/Q353) and PAI-1 (HindIII) genes were measured in men and women aged 60-79 years, together with their plasma levels. Using widely accepted criteria, 88 subjects were identified as having peripheral arterial disease (PAD), 195 having coronary artery disease (CAD) and 423 subjects comprised a “healthy” group. The -455AA genotype of the fibrinogen gene was found to be more frequent among those subjects with PAD. This genotype also showed the highest plasma fibrinogen levels in both disease groups and in the healthy group. Using logistic regression, after adjustment for age, sex, smoking and plasma level, the -455AA genotype was associated with over twice the risk of PAD compared with the -455GG genotype, the odds ratio reaching marginal significance (p″0.10). Combining those with genotype -455AA with the heterozygotes in order to increase the power of the study resulted in a more significant multiple-adjusted risk of PAD (p″0.05). These data provide evidence that a polymorphism of the β fibrinogen gene is associated with an increased risk of peripheral atherosclerosis.

Full Text

References

References
1 Wilhelmsen L, Svardsudd K, Korsan-Bengsten K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 311: 501-5.
2 Stone MC, Thorp JM. Plasma fibrinogen: a major coronary risk factor. J R Coll Gen Pract 1985; 35: 565-9.
3 Meade TW, Ruddock V, Stirling Y, Chakrabarti RR, Miller GJ. Fibrinolytic activity, clotting factors and long-term incidence of ischaemic haert disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-9.
4 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease: the Framingham Study. JAMA 1987; 258: 1183-6.
5 Yarnell JWG, Baker IA, Sweetnam PM, Bainton D, O’Brien JR, Whitehead PJ, Elwood PC. Fibrinogen, viscosity and white blood cell count are major risk factors for ischaemic heart disease: the Caerphilly and Speedwell Collaborative Heart Disease Studies. Circulation 1991; 83: 836-44.
6 Assmann G, Cullen P, Heinrich J, Schulte H. Haemostatic variables in the prediction of coronary risk: results from the 8-year follow-up of healthy men in the Munster Heart Study (PROCAM). Prospective Cardiovascular Munster Study. Isr J Med Sci 1996; 32: 364-70.
7 Lowe GDO, Lee AJ, Rumley A, Price JF, Fowkes FGR. Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study. Br J Haematol 1997; 96: 168-73.
8 Aznar J, Estelles A, Tormo G, Sapena P, Tormo V, Blanch S, Espana F. Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary heart disease. Br Heart J 1988; 59: 535-41.
9 Hamsten A, De Faire U, Walldius G, Dahlen G, Szamos A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9.
10 Thomas AE, Green FR, Kelleher CH, Wilkes HC, Brennan PJ, Meade TW, Humphries SE. Variation in the promoter region of the β fibrinogen gene is associated with plasma fibrinogen levels in smokers and non-smokers. Thromb Haemost 1991; 65: 487-90.
11 Fowkes FGR, Connor JM, Smith FB, Wood J, Donnan PT, Lowe GDO. Fibrinogen genotype and risk of peripheral atherosclerosis. Lancet 1992; 339: 693-6.
12 Iso H, Folsom AR, Winkelmann JC, Koike K, Harada S, Greenberg B, Sato S, Shimamoto T, Iida M, Komachi Y. Polymorphisms of the beta fibrinogen gene and plasma fibrinogen concentration in Caucasian and Japanese population samples. Thromb Haemost 1994; 73: 106-11.
13 de Maat MPM, de Knijff P, Green FR, Thomas AE, Jespersen J, Kluft C. Gender-related association between β-fibrinogen genotype and plasma fibrinogen levels and linkage disequilibrium at the fibrinogen locus in Greenland Inuit. Arterioscler Thromb Vasc Biol 1995; 15: 856-60.
14 Behague I, Poirier O, Nicaud V, Evans A, Arveiler D, Luc G, Cambou J-P, Scarabin P-Y, Bara L, Green F, Cambien F. β fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary heart disease in patients with myocardial infarction. The ECTIM study. Circulation 1996; 93: 440-9.
15 Sosef MN, Bosch JG, van Oostayen J, Visser T, Rieber JHC, Rosendaal FR. Relation of plasma coagulation factor VII and fibrinogen to carotid artery intima-media thickness. Thromb Haemost 1994; 72: 250-4.
16 Lane A, Green F, Scarabin PY, Nicaud V, Bara L, Humphries S, Evans A, Lug G, Cambou JP, Arveiler D, Cambien F. Factor VII Arg/Gln 353 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.
17 Iacoviello L, Castelnuovo AD, de Knijff P, D’Orazio A, Amore C, Arboret-ti R, Kluft C, Donati MB. Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction. N Engl J Med 1998; 338: 79-85.
18 Green F, Kelleher C, Wilkes H, Temple A, Meade TW, Humphries S. A common genetic polymorphism associated with lower coagulation factor VII levels in healthy individuals. Arterioscler Thromb. 1991; 11: 540-6.
19 Lane A, Cruickshank JK, Mitchell J, Henderson A, Humphries S, Green F. Genetic and environmental determinants of factor VII coagulant activity in ethnic groups at differing risk of coronary heart disease. Atherosclerosis 1992; 94: 43-50.
20 Humphries SE, Lane A, Green FR, Cooper J, Miller GJ. Factor VII coagulant activity and antigen levels in healthy men are determined by interaction between factor VII genotype and plasma triglyceride concentration. Arterioscler Thromb 1994; 14: 193-8.
21 Kario K, Narita N, Matsuo T, Kayaba K, Tsutsumi A, Matsuo M, Miyata T, Shimada K. Genetic determinants of plasma factor VII activity in the Japanese. Thromb Haemost 1995; 73: 617-22.
22 Meilahn E, Ferrell R, Kiss J, Temple A, Green F, Humphries S, Kuller L. Genetic determination of coagulation factor VIIc levels among healthy middle-aged women. Thromb Haemost 1995; 73: 623-5.
23 Dawson S, Hamsten A, Wiman B, Henney A, Humphries S. Genetic variation at the plasminogen activator inhibitor-1 locus is associated with altered levels of plasma plasminogen activator inhibitor-1 activity. Arterioscler Thromb 1991; 11: 183-90.
24 Eriksson P, Kallin B, van’t Hooft FM, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen activator 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851-5.
25 Iacoviello L, Burzotta F, Di Castelnuovo A, Marchioli R, Donati MB. The 4G/5G polymorphism of the PAI-1 promoter gene as a risk factor for myocardial infarction: a meta-analysis approach. Blood Coag Fibrinolysis 1997; 8: 20 (abstract).
26 Ridker PM, Hennekens CH, Lindpainter K, Stampfer MJ, Miletich JP. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter region of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation 1997; 95: 59-62.
27 Fowkes FGR, Housley E, Cawood EHH, MacIntyre CCA, Ruckley CV, Prescott RJ. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol 1991; 20: 384-91.
28 Rose GA. The diagnosis of ischaemic heart pain and intermittent claudication in field surveys. Bull WHO 1962; 27: 645-58.
29 Prineas RJ, Crow RS, Blackburn H. The Minnesota Code Manual of Electrocardiographic Findings: Standards and Procedures for Measurement and Classification. London: John Wright; 1982
30 Gillum RF, Fortmann SP, Prineas RJ, Kottke TE. International diagnostic criteria for acute myocardial infarction and acute stroke. Am Heart J 1984; 108: 150-8.
31 Leng GC, Lee AJ, Fowkes FGR, Whiteman M, Dunbar J, Housley E, Ruckley CV. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol 1996; 25: 1172-81.
32 Lowe GDO, Fowkes FGR, Dawes J, Donnan PT, Lennie SE, Housley E. Blood viscosity, fibrinogen and activation of coagulation and leucocytes in peripheral arterial disease and the normal population in the Edinburgh Artery Study. Circulation 1993; 87: 1915-20.
33 Klinger KW, Winqvist R, Riccio A. Plasminogen activator inhibitor type 1 gene is located at region q21.3-q22 of chromosome 7 and genetically linked with cystic fibrosis. Proc Natl Acad Sci USA 1987; 84: 8548-52.
34 Humphries SE, Cook M, Dubowitz M, Striling Y, Meade TW. Role of genetic variation at the fibrinogen locus in determination of plasma fibrinogen concentration. Lancet 1987; I: 1452-4.
35 Carter AM, Ossei-Gerning N, Wilson IJ, Grant PJ. Association of the platelet PI^A polymorphism of glycoprotein IIb/IIIa and the fibrinogen Bβ 448 polymorphism with myocardial infarction and extent of coronary artery disease. Circulation 1997; 96: 1424-31.
36 Green F, Hamsten A, Blomback M, Humphries S. The role of β-fibrinogen genotype in determining plasma fibrinogen levels in young survivors of myocardial infarction and healthy controls from Sweden. Thromb Haemost 1993; 70: 915-20.
37 Humphries SE, Ye S, Talmud P, Bara L, Wilhelmsen L. Tiret L on behalf of the European Atherosclerosis Research Study (EARS) group. European. Atherosclerosis Research Study: genotype at the fibrinogen locus (G^–455 -A β gene) is associated with differences in plasma levels in young men and women from different regions in Europe. Arterioscler Thromb Vasc Biol 1995; 15: 96-104.
38 Thomas AE, Green FR, Lamlum H, Humphries SE. The association of combined α and β fibrinogen genotype on plasma fibrinogen levels in smokers and non-smokers. J Med Genet 1995; 32: 585-9.
39 Thomas AE, Green FR, Humphries SE. Association of genetic variation at the b-fibrinogen gene locus and plasma fibrinogen levels; interaction between allele frequency of the G/A^–455 polymorphism, age and smoking. Clin Genet 1996; 50: 184-90.
40 Berg K, Kierulf P. DNA polymorphisms at fibrinogen loci and plasma fibrinogen concentration. Clin Genet 1989; 36: 229-35.
41 Humphries SE, Panahloo A, Montgomery HE, Green F, Yudkin J. Gene-environment interaction in the determination of levels of haemostatic variables involved in thrombosis and fibrinolysis. Thromb Haemost 1997; 78: 457-61.
42 Scarabin PY, Bara L, Ricard S, Poirier O, Cambou JP, Arveiler D, Lug G, Evans AE, Samama MM, Cambien F. Genetic variation at the β-fibrinogen locus in relation to plasma fibrinogen concentrations and risk of myocardial infarction. The ECTIM Study. Arterioscler Thromb 1993; 13: 886-91.
43 Cortellaro M, Boscetti C, Cofrancesco E, Zanussi C, Catalano M, de Gaetano G, Gabrielli L, Lombardi B, Specchia G, Tavazzi L. The PLAT Study: haemostatic function in relation to atherothrombotic events in vascular disease patients: principal results. Arterioscler Thromb 1992; 12: 1063-70.
44 Folsom AR, Wu KK, Shahar E, Davis CE. Association of haemostatic variables with prevalent cardiovascular disease and asymptomatic carotid artery atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Arterioscler Thromb 1993; 13: 1829-36.
45 Smith FB, Lee AJ, Fowkes FGR, Price JF, Rumley A, Lowe GDO. Haemostatic factors as predictors of ischaemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol 1997; 17: 3321-5.
46 Junker R, Heinrich J, Schulte H, van de Loo J, Assmann G. Coagulation factor VII and the risk of coronary heart disease in healthy men. Arterioscler Thromb Vasc Biol 1997; 17: 1539-44.
47 Miller GJ, Stirling Y, Esnouf MP, Heinrich J, van de Loo J, Kienast J, Wu KK, Morrissey JH, Meade TW, Martin JC, Imeson JD, Cooper JA, Finch A. 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.
48 Bentzen J, Bladbjerg EM, de Matt MPM, Marckmann P. Plasma factor VII levels are determined by polymorphisms in the factor VII gene. Fibrinolysis 1996; 10 (02) Suppl 17-8.
49 de Maat MPM, Green F, de Knijff P, Jespersen J, Kluft C. Factor VII polymorphisms in populations with different risks of cardiovascular disease. Arterioscler Thromb Vasc Biol 1997; 17: 1918-23.
50 Silveira A, Green F, Karpe F, Blombäck MM, Humphries S, Hamsten A. Elevated levels of factor VII activity in the postprandial state: effect of factor VII Arg-Gln polymorphism. Thromb Haemost 1994; 72: 734-9.
51 Juhan-Vague I, Alessi MC. Plasminogen activator inhibitor-1 and athero-thrombosis. Thromb Haemost 1993; 70: 138-43.
52 Juhan-Vague I, Pyke SD, Alessi MC, Jespersen J, Haverkate F, Thompson SG. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectors. ECAT Study Group. Circulation 1996; 94: 2057-63.
53 Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Shen C, Newcomer LM, Goldhaber SZ, Hennekens CH. Baseline fibrinolytic state and the risk of future venous thrombosis: a prospective study of endogenous tissue-type plasminogen activator and plasminogen activator inhibitor. Circulation 1992; 85: 1822-7.
54 Lowe GDO, Yarnell JWG, Sweetnam PM, Rumley A, Thomas HF, Elwood PC. Fibrin D-dimer, tissue plasminogen activator, plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study. Thromb Haemost 1998; 79: 129-33.
55 Henry M, Chomiki N, Scarabin PY, Alessi C, Peiretti F, Arveiler D, Ferrieres J, Evans A, Amouyel P, Poirier O, Cambien F, Juhan-Vague I. Five frequent polymorphisms of the PAI-1 gene. Lack of association between genotypes, PAI activity, and triglyceride levels in a healthy population. Arterioscler Thromb Vasc Biol 1997; 17: 851-8.
56 Mansfield MW, Stickland MH, Grant PJ. Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasian patients with non-insulin dependent diabetes mellitus. Thromb Haemost 1995; 74: 842-7.
57 Mansfield MW, Stickland MH, Carter AM, Grant PJ. Polymorphisms of the plasminogen activator inhibitor-1 gene and type 1 and type 2 diabetes, and in patients with diabetic retinopathy. Thromb Haemost 1994; 71: 731-6.
58 Iacoviello L, Zito F, Di Castelnuovo A, de Maat M, Kluft C, Donati MB. Contribution of factor VII, fibrinogen and fibrinolytic components to the risk of ischaemic cardiovascular disease: their genetic determinants. Fibrinolysis Proteolysis 1998; 12: 259-76.