doi: 10.1161/hy1101.099478
(Hypertension. 2001;38:1199.)
© 2001 American Heart Association, Inc.
Fourth International Seminar on Cardiovascular Biology |
Genes Encoding Fibrinogen and Cardiovascular Risk
From the "Angela Valenti" Laboratory of Genetic and Environmental Risk Factors for Thrombotic Disease, Department of Vascular Medicine and Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.
Correspondence to Licia Iacoviello, MD, PhD, "Angela Valenti" Laboratory of Genetic and Environmental Risk Factors for Thrombotic Disease, Department of Vascular Medicine and Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy. E-mail: iaco{at}cmns.mnegri.it
Abstract
Abstract—— The role of fibrinogen in cardiovascular disease has been extensively studied, and meta-analyses have definitively confirmed that high levels of fibrinogen are associated with an increased risk of the disease. In recent years, several polymorphisms have been identified in the fibrinogen chain genes that contribute to determine the levels of fibrinogen in the general population. The fibrinogen ß-chain gene has been more extensively studied because the ß-chain synthesis is the limiting step in the production of mature fibrinogen. Overall, the studies show an association between ß-fibrinogen chain polymorphisms and the levels of fibrinogen. In contrast, the majority of the studies did not find any relation with the risk of cardiovascular disease. The individual responses to gender or to environmental stimuli such as smoking, physical exercise, or infections may be genetically determined, and genetic variability underlies changes in biological reactions that contribute to differences in cardiovascular risk. In the future, gene-environment interactions should be considered in evaluating the relevance of genetic variations on the risk of cardiovascular disease.
Key Words: fibrinogen • polymorphisms • gene-environment interactions • risk factors • cardiovascular disease
After the first evidence made in the early 1980s by Meade et al1 in the Northwick Park Heart Study (NPHS), the role of fibrinogen as a predictor of primary and secondary ischemic coronary events has been demonstrated by several epidemiological studies.2–5
Three meta-analyses have been published on the association between fibrinogen and cardiovascular disease: all agree on the finding that high fibrinogen levels are associated with an increased risk of disease.6–8 The last of them8 reviewed 18 prospective studies on 
4000 cases of coronary heart disease followed for a mean of 8 years: fibrinogen levels in the top third were associated with an odds ratio of 1.8 (95% confidence interval [CI], 1.6 to 2.0). These results definitively confirmed the importance of fibrinogen, because they assemble a large number of prospective studies, weighed for possible confounders.
Many pieces of evidence make plausible a causal contribution of fibrinogen to cardiovascular disease. This protein is crucial in the process of thrombus formation and evolution, and its levels are influenced by several conventional risk factors. Fibrinogen is the last target of coagulation: its lysis by thrombin produces soluble fibrin fragments that are then stabilized in a clot by factor XIII. It is a mediator of platelet aggregation and a determinant of plasma viscosity. Fibrinogen is an acute phase protein, synthesized in the liver, the plasma levels of which acutely rise during inflammatory conditions. Fibrinogen levels increase with age, pregnancy, use of oral contraceptives, menopause, and obesity. Smoking habits, infections, hypertension, and diabetes are associated with increased levels of fibrinogen, whereas physical activity, moderate alcohol consumption, and fish intake reduce fibrinogen levels.9 Furthermore, fibrinogen can be considered as a common pathway through which risk factors may act in promoting arterial disease.
More recently, the study of genetics added new insights to this complex picture of interactions, showing that the variation of fibrinogen levels in a general population can be explained in part by variations at fibrinogen gene loci.
Genetic Determinants of Fibrinogen Levels
Fibrinogen is 340-kDa dimeric glycoprotein; each dimer consists of 3 different polypeptide chains known as 
-, ß-, and 
-chains, linked by disulfide bonds. The 3 polypeptide chains are encoded by 3 different genes clustered on chromosome 4 in region q28. The 3 genes, ordered as , , and ß, span a distance of 50 kb, with the direction of transcription of ß-gene opposite that the - and -genes.10
Many polymorphisms of this cluster have been identified; however, the most studied have been those located in the ß-chain fibrinogen gene (Figure). Indeed, in vitro studies have suggested that ß-chain synthesis limits the rate of production of mature fibrinogen.11 As a consequence, polymorphisms affecting the production of this chain would more likely influence the levels of fibrinogen. Overall, the studies show a strong association between ß-chain fibrinogen genotypes and its plasma concentrations.
|
A DNA variation of the ß-fibrinogen gene has been detected at the 3' region, by the BclI restriction enzyme (BclI polymorphism), as a biallelic polymorphism, with a frequency of the rare B2 allele of 0.18 in the general population. The rare B2B2 genotype has been consistently associated with levels of fibrinogen 15% to 20% higher than that of the B1B1 genotype.12–16 However, because of its location on the gene, it would be difficult to consider a biological function for this polymorphism, which has been mainly considered as a marker for another locus on the fibrinogen gene.
BclI polymorphism is in linkage disequilibrium with the G/A sequence variation at position -455, detected in the promoter region, by the HaeIII restriction enzyme,17,18 which is more compatible with a modified transcription of the gene. It is, indeed, located in the promoter, close to responsive elements (IL-6 and the HNF-1 elements).
Out of 23 pertinent publications13,17–38 between 1991 and 2001, all the studies, but 4,26,29,33,37 are consistent with the finding that the A-455 allele, which is present in 20% of the general population, is associated with increased levels of fibrinogen of 0.30 g/L compared with homozygotes for the G allele (Table). Experimental studies have demonstrated that the GÅ substitution at -455 has a substantial effect on the basal and stimulated rate of transcription of the ß-chain gene, the A allele being associated with a significant increase in the promoter activity.34,39 The -854 G/A polymorphism has also been independently associated with increased transcription of ß-fibrinogen in vitro and can also contribute to the regulation plasma fibrinogen levels.34 However, a recent study, reporting a different allelic association between -455 G/A and -148 C/T in different ethnic groups living in England, showed that the T allele rather than the A allele was associated with high fibrinogen levels.40
|
Fibrinogen Polymorphisms and Risk of Cardiovascular Disease
Although the association between fibrinogen polymorphisms and fibrinogen levels has been consistently reported, their association with the risk of cardiovascular disease is still largely debated.
The involvement of BclI fibrinogen polymorphism in the risk of ischemic vascular disease has been confirmed by some studies,12,13,15 although others gave negative results.33 Fowkes et al12 first described an association between the B2 allele and the risk of peripheral arterial disease. In the ECTIM (Etude Cas-Temoin de l’Infarctus du Myocarde) study, it was related with the severity of coronary artery disease rather than with myocardial infarction.13 In cohorts of Italian patients, carriers of the B2B2 genotype showed a 2.4-fold increased risk of myocardial infarction. However, the risk was present only when patients with a family history of ischemic vascular disease were selected.15,16
Only few studies have found an association between -455 G/A polymorphism and the risk of ischemic vascular disease (Table).25,26,32,35,36 In particular, out of 14 studies in which the relation between -455 G/A polymorphism and the risk was evaluated, only 5 reported the presence of an association. None of the latter were related to thrombosis in coronary arteries. However, 2 groups showed an association with the risk of cardiovascular disease in patients with non–insulin-dependent diabetes, 26,35 one with peripheral arterial disease,32 one with deep venous thrombosis,25 and the last one with large vessel cerebrovascular disease.36 An additional study documented that the -455 G/A polymorphism was related to the progression of cardiovascular disease, in patients with hypercholesterolemia.41
The number of subjects included in the different studies has never been sufficient to detect any statistically significant association. Indeed, considering the results of the meta-analyses of fibrinogen, it can be assumed that an increase in 1 g/L of fibrinogen accounts for a relative risk of 1.8 in the risk for coronary heart disease. Nevertheless, homozygosity for the A-455 allele increases of 0.30 g/L the levels of fibrinogen, which assuming linearity in logarithm of relative risk corresponds to a relative risk of 1.20. To have the power of 80% to detect such an increase, a case control study should recruit 11 600 cases and a corresponding number of controls. This size has never been reached in the studies published until now. However, it is relevant to consider the cost-effectiveness of performing such a large study with a single polymorphism to demonstrate an association that, in any case, would be of poor clinical relevance. New strategies, such as considering multiple haplotypes or identifying new polymorphisms in less explored fibrinogen gene sequences, should be also undertaken to definitively define the role of fibrinogen polymorphisms in the risk of cardiovascular disease.
Gene-Environment Interactions and Fibrinogen Levels
Rather than directly affect the levels of proteins, polymorphisms can amplify the effect of environmental or intermediate conditions on the final phenotype. An individual with a genetic predisposition might have a stronger response when exposed to a specific stimulus, which translates in the synthesis of higher levels of fibrinogen.
The genetic control of fibrinogen has to be considered together with environmental factors: indeed, fibrinogen genotypes may interact with cigarette smoking,17 gender,18,22 and physical activity27 in determining the increase in fibrinogen levels.
A different association has been found between -455 G/A or BclI polymorphisms and fibrinogen levels in women than in men.18,21,22 The effect of the A allele of the -455 G/A polymorphism on fibrinogen levels was additive in men, whereas it showed a dominant behavior in women. When menopausal status and hormone replacement therapy (HRT) were considered, the dominant effect of the A allele was evident only in postmenopausal women not taking hormones, whereas in both premenopausal and postmenopausal women treated with HRT, the effect of the A allele was additive, as observed in men.22
These findings suggest that the effects of hormones or other gender-specific factors on the synthesis of fibrinogen is modulated by genetic variance at the promoter levels, that can differently regulate the activation repression of fibrinogen gene transcription.
The fibrinogen genetic asset can also regulate the relationship between physical activity and fibrinogen levels. An inverse dose-response relationship has been described between regular physical exercise and fibrinogen levels,42 although an intensive, strenuous exercise is associated with an acute rise in fibrinogen levels.27 The increase lasts several days, probably because of a continuous fibrinogen production. However, this phenomenon varies according to the G/A -455 polymorphism of the fibrinogen ß-chain gene. After 2 days of strenuous military exercise, an increase in fibrinogen levels (compared with the concentration at pretraining) was recorded and found maximal at the second day after the exercise. This effect was significantly stronger in the AA homozygotes compared with heterozygotes and GG homozygotes.27
Vaisanen et al43 showed that physical activity levels explained up to 9% of fibrinogen variance in carriers of the B2 allele of the BclI ß-chain gene polymorphism, whereas it had only a marginal effect in carriers of the common B1 fibrinogen genotype. Similar results were shown for polymorphisms in the -chain gene of fibrinogen in postmenopausal women44 and in middle-aged men.45
Gene-Environment Interactions and Risk of Cardiovascular Disease
Beside their effect on fibrinogen levels, fibrinogen polymorphisms can also modulate the relationship between environmental risk factors and the risk of cardiovascular disease. Helicobacter pylori (HP) infection has been associated with a higher risk to develop ischemic heart disease, although the results are controversial.46 Zito et al16 showed that the BclI polymorphisms of ß-fibrinogen gene modulated the effect of HP on both fibrinogen levels and the risk of myocardial infarction.
HP, a life-long bacterial infection, was found to be associated with chronically increased plasma levels of fibrinogen. However, the effect was stronger in carriers of B2 allele. Carriership of the B2 allele also amplified the effect of seropositivity for HP16 on the risk of myocardial infarction. Indeed, patients with both seropositivity for HP and carriers of B2 genotype showed an additional increase in the risk of myocardial infarction compared with that of subjects affected by HP but homozygous for the B1 allele.
Conclusions
The prognostic role of fibrinogen on the risk of cardiovascular disease has been extensively proved. Genetic determinants, through a modulation of fibrinogen levels, might contribute to the risk of cardiovascular disease. Epidemiological studies, however, failed to demonstrate this relation, probably because the effect, if present, is relatively small and needs larger and very selected populations to be detected. Moreover, it becomes more evident that gene-environment interactions are determinant in understanding the role of genetic polymorphisms on the risk of disease. Indeed, genetic variability, rather than playing any direct role, influences a different individual susceptibility to environmental risk factors.
In the future, efforts should be made in defining the mechanism of these interactions and their role in determining the risk of cardiovascular disease.
Acknowledgments
We thank Dr Giovanni de Gaetano for critical reading this manuscript. This work was supported by a grant from Telethon (Rome, Italy), contract No. E.1005, and by the Italian Ministry of Health.
Received August 8, 2001; first decision August 15, 2001; accepted September 10, 2001.
References
1. Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986; 2: 533–537.[Medline] [Order article via Infotrieve]
2. Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984; 311: 501–505.[Abstract]
3.
Heinrich J, Balleisen L, Schulte H, Assmann G, van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk: results from the PROCAM study in healthy men. Arterioscler Thromb. 1994; 14: 54–59.
4. Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet. 1993; 342: 1076–1079.[Medline] [Order article via Infotrieve]
5. Haines AP, Howarth D, North WR, Goldenberg E, Stirling Y, Meade TW, Raftery EB, Millar Craig MW. Haemostatic variables and the outcome of myocardial infarction. Thromb Haemost. 1983; 50: 800–803.[Medline] [Order article via Infotrieve]
6.
Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of literature. Ann Intern Med. 1993; 118: 956–963.
7.
Maresca G, Di Blasio A, Marchioli R, Di Minno G. Measuring plasma fibrinogen to predict stroke and myocardial infarction: an update. Arterioscler Thromb Vasc Biol. 1999; 19: 1368–1377.
8.
Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998; 279: 1477–1482.
9.
Folsom AR, Wu KK, Shahar E, Davis CE. Association of hemostatic variables with prevalent cardiovascular disease and asymptomatic carotid artery atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study Investigators. Arterioscler Thromb. 1993; 13: 1829–1836.
10.
Henry I, Uzan G, Weil D, Nicolas H, Kaplan JC, Marguerie C, Kahn A, Junien C. The genes coding for -, ß-, and -chains of fibrinogen map to 4q2. Am J Hum Genet. 1984; 36: 760–768.[Medline]
[Order article via Infotrieve]
11.
Yu S, Sher B, Kudryk B, Redman CM. Fibrinogen precursors: order of assembly of fibrinogen chains. J Biol Chem. 1984; 259: 10574–10581.
12. Fowkes FG, Leng GC, Donnan PT, Deary IJ, Riemersma RA, Housley E. Serum cholesterol, triglycerides, and aggression in the general population. Lancet. 1992; 340: 995–998.[Medline] [Order article via Infotrieve]
13.
Behague I, Poirier O, Nicaud V, Evans A, Arveiler D, Luc G, Cambou JP, Scarabin PY, Bara L, Green F, Cambien F. ß-Fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction: the ECTIM Study Etude Cas-Temoins sur l’Infarctus du Myocarde. Circulation. 1996; 93: 440–449.
14. Thomas AE, Green FR, Humphries SE. Association of genetic variation at the ß-fibrinogen gene locus and plasma fibrinogen levels; interaction between allele frequency of the G/A-455 polymorphism, age and smoking. Clin Genet. 1996; 50: 184–190.[Medline] [Order article via Infotrieve]
15.
Zito F, Di Castelnuovo A, Amore C, D’Orazio A, Donati MB, Iacoviello L. BclI polymorphism in the fibrinogen ß-chain gene is associated with the risk of familial myocardial infarction by increasing plasma fibrinogen levels: a case-control study in a sample of GISSI-2 patients. Arterioscler Thromb Vasc Biol. 1997; 17: 3489–3494.
16. Zito F, Di Castelnuovo A, D’Orazio A, Negrini R, De Lucia D, Donati MB, Iacoviello L. Helicobacter pylori infection and the risk of myocardial infarction: role of fibrinogen and its genetic control. Thromb Haemost. 1999; 82: 14–18.
17.
Thomas A, Lamlum H, Humphries S, Green F. Linkage disequilibrium across the fibrinogen locus as shown by five genetic polymorphisms, G/A-455 (HaeIII), C/T-148 (HindIII/AluI), T/G+1689 (AvaII), and Bc1I (ß-fibrinogen) and TaqI (-fibrinogen), and their detection by PCR. Hum Mutat. 1994; 3: 79–81.[Medline]
[Order article via Infotrieve]
18.
de Maat MP, de Knijff P, Green FR, Thomas AE, Jespersen J, Kluft C. Gender-related association between ß-fibrinogen genotype and plasma fibrinogen levels and linkage disequilibrium at the fibrinogen locus in Greenland Inuit. Arterioscler Thromb Vasc Biol. 1995; 15: 856–860.
19. Scarabin PY, Bara L, Ricard S, Poirier O, Cambou JP, Arveiler D, Luc G, Evans AE, Samama MM, Cambien F. Genetic variation at the ß-fibrinogen locus in relation to plasma fibrinogen concentrations and risk of myocardial infarction: the ECTIM. Study Arterioscler Thromb. 1993; 13: 886–891.
20. Green F, Hamsten A, Blomback M, Humphries S. The role of ß-fibrinogen genotype in determining plasma fibrinogen levels in young survivors of myocardial infarction and healthy controls from Sweden. Thromb Haemost. 1993; 70: 915–920.[Medline] [Order article via Infotrieve]
21.
Humphries SE, Ye S, Talmud P, Bara L, Wilhelmsen L, Tiret L. European Atherosclerosis Research Study: genotype at the fibrinogen locus (G-455-A ß) is associated with differences in plasma fibrinogen levels in young men and women from different regions in Europe: evidence for gender-genotype-environment interaction. Arterioscler Thromb Vasc Biol. 1995; 15: 96–104.
22.
Tybjaerg-Hansen A, Agerholm-Larsen B, Humphries SE, Abildgaard S, Schnohr P, Nordestgaard BG. A common mutation (G-455
A) in the ß-fibrinogen promoter is an independent predictor of plasma fibrinogen, but not of ischemic heart disease: a study of 9,127 individuals based on the Copenhagen City Heart Study. J Clin Invest. 1997; 99: 3034–3039.[Medline]
[Order article via Infotrieve]
23. Gardemann A, Schwartz O, Haberbosch W, Katz N, Weiss T, Tillmanns H, Hehrlein FW, Waas W, Eberbach A. Positive association of the ß fibrinogen H1/H2 gene variation to basal fibrinogen levels and to the increase in fibrinogen concentration during acute phase reaction but not to coronary artery disease and myocardial infarction. Thromb Haemost. 1997; 77: 1120–1126.[Medline] [Order article via Infotrieve]
24.
Wang XL, Wang J, McCredie RM, Wilcken DE. Polymorphisms of factor V, factor VII, and fibrinogen genes: relevance to severity of coronary artery disease. Arterioscler Thromb Vasc Biol. 1997; 17: 246–251.
25. Koster T, Rosendaal FR, Reitsma PH, van der Velden PA, Briet E, Vandenbroucke JP. Factor VII and fibrinogen levels as risk factors for venous thrombosis: a case-control study of plasma levels and DNA polymorphisms: the Leiden Thrombophilia Study (LETS). Thromb Haemost. 1994; 71: 719–722.[Medline] [Order article via Infotrieve]
26. Carter AM, Mansfield MW, Stickland MH, Grant PJ. ß-fibrinogen gene-455 G/A polymorphism and fibrinogen levels: risk factors for coronary artery disease in subjects with NIDDM. Diabetes Care. 1996; 19: 1265–1268.[Abstract]
27.
Montgomery HE, Clarkson P, Nwose OM, Mikailidis DP, Jagroop IA, Dollery C, Moult J, Benhizia F, Deanfield J, Jubb M, World M, McEwan JR, Winder A, Humphries S. The acute rise in plasma fibrinogen concentration with exercise is influenced by the G-453-A polymorphism of the ß-fibrinogen gene. Arterioscler Thromb Vasc Biol. 1996; 16: 386–391.
28.
Henry JA, Bolla M, Osmond C, Fall C, Barker DJ, Humphries SE. The effects of genotype and infant weight on adult plasma levels of fibrinogen, factor VII, and LDL cholesterol are additive. J Med Genet. 1997; 34: 553–558.
29. Margaglione M, Di Minno G, Grandone E, Vecchione G, Celentano E, Cappucci G, Giordano M, Simone P, Fusilli S, Panico S, Mancini M. Raised plasma fibrinogen concentrations in subjects attending a metabolic ward–relation to family history and vascular risk factors. Thromb Haemost. 1995; 73: 579–583.[Medline] [Order article via Infotrieve]
30.
Heinrich J, Funke H, Rust S, Schulte H, Schonfeld R, Kohler E, Assmann G. Impact of the polymorphisms in the - and ß-fibrinogen gene on plasma fibrinogen concentrations of coronary heart disease patients. Thromb Res. 1995; 77: 209–215.[Medline]
[Order article via Infotrieve]
31. Margaglione M, Cappucci G, Colaizzo D, Pirro L, Vecchione G, Grandone E, Di Minno G. Fibrinogen plasma levels in an apparently healthy general population: relation to environmental and genetic determinants. Thromb Haemost. 1998; 80: 805–810.[Medline] [Order article via Infotrieve]
32. Lee AJ, Fowkes FG, Lowe GD, Connor JM, Rumley A, Fibrinogen, factor VII, and PAI-1 genotypes and the risk of coronary and peripheral atherosclerosis: Edinburgh Artery Study. Thromb Haemost. 1999; 81: 553–560.[Medline] [Order article via Infotrieve]
33. Doggen CJ, Bertina RM, Cats VM, Rosendaal FR. Fibrinogen polymorphisms are not associated with the risk of myocardial infarction. Br J Haematol. 2000; 110: 935–938.[Medline] [Order article via Infotrieve]
34.
Van’t Hooft FM, von Bahr SJF, Silveira A, Iliadou A, Eriksson P, Hamsten A. Two common, functional polymorphisms in the promoter region of the ß-fibrinogen gene contribute to regulation of plasma fibrinogen concentration. Arterioscler Thromb Vasc Biol. 1999; 19: 3063–3070.
35. Lam KS, Ma OC, Wat NM, Chan LC, Janus ED. ß-fibrinogen gene G/A-455 polymorphism in relation to fibrinogen concentrations and ischaemic heart disease in Chinese patients with type II diabetes. Diabetologia. 1999; 42: 1250–1253.[Medline] [Order article via Infotrieve]
36.
Kessler C, Spitzer C, Stauske D, Mende S, Stadlmuller J, Walther R, Rettig R. The apolipoprotein E and ß-fibrinogen G/A-455 gene polymorphisms are associated with ischemic stroke involving large-vessel disease. Arterioscler Thromb Vasc Biol. 1997; 17: 2880–2884.
37. Vaisanen S, Rauramaa R, Penttila I, Rankinen T, Gagnon J, Perusse L, Chagnon M, Bouchard C. Variation in plasma fibrinogen over one year: relationships with genetic polymorphisms and non-genetic factors. Thromb Haemost. 1997; 77: 884–889.[Medline] [Order article via Infotrieve]
38. Folsom AR, Aleksic N, Ahn C, Boerwinkle E, Wu KK. ß fibrinogen gene -455G/A polymorphosm and coronary heat disease incidence: the Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol. 2001; 11: 166–170.[Medline] [Order article via Infotrieve]
39.
Brown ET, Fuller GM. Detection of a complex that associates with the ß fibrinogen G-455-A polymorphism. Blood. 1998; 92: 3286–3293.
40.
Cook DG, Cappuccio FP, Atkinson RW, Wicks PD, Chitolie A, Nakandakare ER, Sagnella GA, Humphries SE. Ethnic differences in fibrinogen levels: the role of environmental factors and the ß fibrinogen gene. Am J Epidemiol. 2001; 153: 799–806.
41.
de Maat MP, Kastelein JJ, Jukema JW, Zwinderman AH, Jansen H, Groenemeier B, Bruschke AV, Kluft C. -455G/A polymorphism of the ß-fibrinogen gene is associated with the progression of coronary atherosclerosis in symptomatic men: proposed role for an acute-phase reaction pattern of fibrinogen: REGRESS group. Arterioscler Thromb Vasc Biol. 1998; 18: 265–271.
42.
Geffken D, Cushman M, Burke G, Polak J, Sakkinen P, Tracy R. Association between physical activity and markers of inflammation in a healthy elderly population. Am J Epidemiol. 2001; 153: 242–250.
43. Vaisanen S, Rauramaa R, Rankinen T, Gagnon J, Couchard C. Physical activity, fitness, and plasma fibrinogen with reference to fibrinogen genotypes. Med Sci Sports Exerc. 1996; 28: 1165–1170.[Medline] [Order article via Infotrieve]
44. Rauramaa R, Vaisanen S, Nissinen A, Rankinen T, Penttila I, Saarikoski S, Tuomilehto J, Gagnon J, Perusse L, Bouchard C. Physical activity, fibrinogen plasma level and gene polymorphisms in postmenopausal women. Thromb Haemost. 1997; 78: 840–844.[Medline] [Order article via Infotrieve]
45.
Rauramaa R, Vaisanen SB, Kuhanen R, Penttila I, Bouchard C. The RsaI polymorphism in the -fibrinogen gene and response of plasma fibrinogen to physical training-a controlled randomised clinical trial in men. Thromb Haemost. 2000; 83: 803–806.[Medline]
[Order article via Infotrieve]
46. Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet. 1997; 350: 430–436.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  E. S. Ganotakis, I. F. Gazi, J. A. Papadakis, I. A. Jagroop, D. R. Nair, and D. P. Mikhailidis The Relationship Between Circulating Fibrinogen and Lipoprotein (a) Levels in Patients With Primary Dyslipidemia Clinical and Applied Thrombosis/Hemostasis, January 1, 2007; 13(1): 35 - 42. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Kathiresan, Q. Yang, M. G. Larson, A. L. Camargo, G. H. Tofler, J. N. Hirschhorn, S. B. Gabriel, and C. J. O'Donnell Common Genetic Variation in Five Thrombosis Genes and Relations to Plasma Hemostatic Protein Level and Cardiovascular Disease Risk Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1405 - 1412. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Staiger, K. Staiger, N. Stefan, H. G. Wahl, F. Machicao, M. Kellerer, and H.-U. Haring Palmitate-Induced Interleukin-6 Expression in Human Coronary Artery Endothelial Cells Diabetes, December 1, 2004; 53(12): 3209 - 3216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Sankar, M. K. Cho, C. M. Condit, L. M. Hunt, B. Koenig, P. Marshall, S. S.-J. Lee, and P. Spicer Genetic Research and Health Disparities JAMA, June 23, 2004; 291(24): 2985 - 2989. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. H Reinhart Fibrinogen - marker or mediator of vascular disease? Vascular Medicine, August 1, 2003; 8(3): 211 - 216. [Abstract] [PDF]
|
|
|
|
|
|
L. H. Kuller Hormone Replacement Therapy and Risk of Cardiovascular Disease: Implications of the Results of the Women's Health Initiative Arterioscler. Thromb. Vasc. Biol., January 1, 2003; 23(1): 11 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Sehnal and J. Slany Fibrinogen--the key to familial CHD or just another shadow in Plato's Allegory? Eur. Heart J., August 2, 2002; 23(16): 1231 - 1233. [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||