© 1997 American Heart Association, Inc.
Articles |
Gender-Specific Associations of the Fibrinogen Bß 448 Polymorphism, Fibrinogen Levels, and Acute Cerebrovascular Disease
From the Unit of Molecular Vascular Medicine, Research School of Medicine, University of Leeds, General Infirmary (A.M.C., A.J.C., P.J.G.), and the Department of Neurology, St James University Hospital (J.M.B), Leeds, UK.
Correspondence to Angela M. Carter, Unit of Molecular Vascular Medicine, Research School of Medicine, G Floor, Martin Wing, General Infirmary at Leeds, Leeds LS1 3EX, UK. E-mail angelac{at}pathology.leeds.ac.uk
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Abstract |
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Abstract Fibrinogen is an independent risk factor for the development of stroke. Factors influencing circulating levels of fibrinogen include age, smoking, gender, and genetic factors. The aim of this study was to determine the relationship between a polymorphism at position 448 of the Bß fibrinogen gene, fibrinogen levels, gender, and the risk of stroke. Fibrinogen levels were determined in 305 patients with stroke, taken within 10 days of the acute event and 3 months later, and in 197 control subjects. Initial fibrinogen levels in patients (4.49 g/L) were significantly higher than at 3 months (3.85 g/L, P<.0001), consistent with resolution of the acute-phase response. At 3 months, levels were only significantly higher than for control subjects in the male patients (3.86 g/L versus 3.31 g/L, P<.0001). Fibrinogen levels were associated with Bß 448 genotype in male patients at 3 months (1/1=3.62 g/L, 1/2+2/2=4.27 g/L, P=.01). There was a significant difference in the genotype distribution in female patients and control subjects (patients: 1/1=95, 1/2=34, 2/2=6; control subjects: 1/1=61, 1/2=50, 2/2=3, P=.008). These data suggest that the mechanisms linking fibrinogen and the development of cerebrovascular disease are different in males and females. In male patients, the increase in fibrinogen levels may be influenced by environmental factors, while in females there may be a functional difference in the fibrinogen molecule unrelated to fibrinogen levels.
Key Words: fibrinogen • gender • stroke • fibrinogen gene polymorphisms
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Introduction |
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Large epidemiological and case control studies have demonstrated that high fibrinogen levels lead to an increased risk of developing cerebrovascular disease,1 2 3 myocardial infarction,4 5 6 and peripheral arterial disease.7 The Gothenburg study1 showed a synergistic effect of fibrinogen and systolic blood pressure in the development of stroke, the highest risk associated with high plasma fibrinogen and systolic hypertension and no increased risk in persons with high systolic hypertension alone. The Northwick Park Heart Study demonstrated that an increase of one SD in fibrinogen levels (0.6 g/L) resulted in an 84% increase in the risk of developing myocardial infarction within 5 years in middle-aged men.4
Fibrinogen is a 340 000-D glycoprotein comprising pairs of three nonidentical polypeptides: A
, Bß and 
chains.8 9 The genes encoding these three polypeptides lie in a 50-kD stretch on the long arm of chromosome 4, the direction of transcription of the ß gene being in the opposite direction to that of the other two.10 The synthesis of the Bß chain is thought to be the rate-limiting step in the secretion of fibrinogen from hepatocytes,11 but an increase in the synthesis of any one of the fibrinogen polypeptide chains leads to an increase in the synthesis of the other two.12
A number of important factors influence circulating levels of fibrinogen, including age, smoking, and gender.13 14 15 Evidence has emerged to indicate a strong genetic component determining fibrinogen levels. Studies have reported as much as 51% of the variation in levels to be due to genetic factors.16 17 Several studies have investigated the relationship between the presence of restriction fragment length polymorphisms of the fibrinogen gene locus and circulating levels of fibrinogen with conflicting results, finding either no relationship or up to 15% of the variation in levels associated with one or more restriction fragment length polymorphisms.18 19 20 21 22 23 A G/A polymorphism at position 448 of the Bß fibrinogen gene has been identified, which codes for an arginine-to-lysine substitution 13 amino acids from the carboxyl terminal of the Bß fibrinogen polypeptide chain.24 25 This polymorphism has been demonstrated to be in strong linkage disequilibrium with the -455 G/A polymorphism in the 5' flanking region of the ß fibrinogen gene,26 which is itself in complete linkage disequilibrium with a -148 C/T polymorphism in the promoter region of the ß fibrinogen gene.27 The role of the Bß 448 polymorphism in relation to the development of vascular disease has not been investigated.
The aim of this study was to determine the relationship between the Bß 448 polymorphism, fibrinogen levels, and the risk of stroke.
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Methods |
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Subjects
Three hundred five white patients with a clinical diagnosis of acute stroke, whose pathological type was confirmed by noncontrast cranial CT scan, were recruited from four hospitals in Leeds. One hundred ninety-seven white control subjects were recruited from Family Health Services Authority general practice registers. Patients and control subjects were classified as smokers if they currently smoked or had ceased to smoke within the last 5 years. All other individuals were classified as nonsmokers. Patients and control subjects gave informed consent according to a protocol approved by the United Leeds Teaching Hospitals Research Ethics Committee. On the basis of the CT scan results, stroke was classified as either ICH or CI. We further subclassified CI according to the Oxfordshire Community Stroke Project classification.28 Subjects presenting with lacunar syndromes (pure sensory, pure motor, sensorimotor stroke, or ataxic hemiparesis) whose CT scan showed an appropriate small, deep infarct or no relevant lesion (LACI) were considered as having probable small-vessel disease. Patients presenting with syndromes that were suggestive of cortical infarction in the carotid territory, either TACI or PACI, were considered as having probable large-vessel infarction. Patients presenting with syndromes referable to the posterior (vertebrobasilar) circulation were separately identified (POCI) and were considered likely to have a mixed vascular pathology. This classification serves to predict the volume of parenchymal damage that is a function of the diameter of the occluded vessel (in descending order TACI, PACI/POCI, LACI).
Analysis of Circulating Factors
Venous blood samples were taken within 10 days of the development of stroke, and whole blood was taken into EDTA and stored for extraction of genomic DNA. Samples for measurement of circulating fibrinogen were taken into 0.1 mol/L trisodium citrate, centrifuged at 2500g at room temperature, and stored at -40°C until analyzed. A further venous blood sample for fibrinogen was taken at least 3 months after the acute event to allow for resolution of the acute phase, and fibrinogen was analyzed with the initial sample by the method of Clauss,29 using a KC10 coagulometer (Amelung). Control subjects gave a single sample for determination of fibrinogen level. Intra-assay and interassay coefficients of variation were 2% and 3.5%, respectively.
DNA Analysis
Genomic DNA was extracted from 10 mL of whole blood taken into EDTA as previously described.30 Fibrinogen Bß 448 genotype was determined by PCR amplification of a 314-bp fragment of DNA, using specific oligonucleotide primers25 in a PTC 100 thermal cycler (Cetus). Standard PCR conditions of 50 pmol each primer, 100 ng DNA, 200 µmol/L each dNTP, 10 mmol/L Tris HCl (pH 8.8), 1.5 mmol/L MgCl, 50 mmol/L KCl, 0.1% Triton X-100, and 0.5 U Dynazyme II DNA polymerase (Flowgen) were used, involving 30 cycles at 93°C for 1 minute for denaturing, 1 minute at 54°C for annealing, and 1 minute at 72°C for extension, followed by a final 5-minute extension time at 72°C. PCR products were subjected to overnight digestion using Mnl I restriction enzyme at 37°C following the manufacturers conditions (New England BioLabs). Restricted DNA products were then separated by 2% agarose gel electrophoresis containing ethidium bromide and visualized by ultraviolet light. Bß 448 genotype was classified as 1/1 (Arg, Arg), 1/2 (Arg, Lys), or 2/2 (Lys, Lys).
Statistics
The distribution of fibrinogen levels was found to be positively skewed and was therefore log transformed to normalize the distribution and allow analysis by parametric tests. Where results were log transformed, they are expressed as geometric mean and antilogged 95% confidence intervals. Age is expressed as median and interquartile range. All other values are expressed as mean (95% confidence intervals). Initial and 3-month fibrinogen levels in patients were compared by paired t test. Patient levels at both visits were compared with those of control subjects by unpaired t test. Ages were compared by Mann-Whitney U tests. To investigate the relationship between fibrinogen levels and genotype, the 1/2 and 2/2 genotype groups were combined, due to the low incidence of the 2/2 genotype, and analyzed by unpaired t tests. Multiple regression analysis was used to identify the determinants of fibrinogen levels in each group. General factorial ANOVA models were used to investigate the possibility of interactions of genotype with gender and smoking on the relationship to levels by creating interaction terms. Genotype distributions were compared by gene counting and 
2 analysis. All statistical analyses were performed using the SPSS for Windows statistical package (SPSS Inc).
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Results |
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Patient and Control Characteristics
Females were significantly older than males in both patient (females, n=149, aged 74 [68 to 82]; males, n=156, aged 72 [62 to 78]; P=.0025) and control (females, n=121, aged 77 [67 to 82]; males, n=76, aged 72[64 to 79]; P=.011) groups, but there was no significant difference in the ages of female patients and control subjects or male patients and control subjects (P>.1). In the patients, 40% of males and 29% of females were smokers, whereas in control subjects, 19% of males and 26% of females were smokers. There were more male than female smokers in the patient group (
2 P=.0001), and more male patients smoked than male control subjects (2 P=.0001). This was not the case among females. There was no difference in body mass index in patients (female=24.2 [22.7 to 26.7], male=24.3 [23.0 to 25.6]) and control subjects (female=25.1 [22.9 to 27.3], male=24.4 [22.5 to 26.3]).
Fibrinogen Levels in Patients and Control Subjects
In the patients followed up after 3 months, fibrinogen levels were significantly higher initially than at the 3-month follow-up (4.36 [4.19 to 4.55] versus 3.85 [3.69 to 4.00], P<.0001). The levels were also significantly higher in patients than in control subjects both initially and at 3 months (P<.001), as shown in Table 1
. In males, fibrinogen levels at both initial and 3-month visits were significantly higher than male control subjects (P<.0001), and 3-month levels were significantly lower than initial levels (P<.0001). In females, initial fibrinogen levels were significantly higher than 3-month levels and levels in control subjects, but at 3 months there was no significant difference between female patient and female control levels.
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Table 2 shows the association between fibrinogen levels and stroke subtypes. Stroke subtype was significantly associated with initial fibrinogen levels, the levels of the TACI group being higher than the other infarction groups (P<.003). When considered by gender, a similar trend was observed but reached significance only in the female group (P=.021). At 3 months there was no association between levels and subtype in any group.
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Genotype Distribution
The genotype distributions of the patients and control subjects as a whole and by gender did not differ significantly from that predicted by Hardy-Weinberg equilibrium and are presented in Table 3. In the patient group as a whole there was no difference in the genotype distribution compared with control subjects (2 P=.086) or in relation to stroke subtype (data not shown). There was no difference in the genotype distributions of male and female patients, male and female control subjects, or male patients and male control subjects. However, there was a significant difference between female patients and female control subjects (2 P=.008), results from the 2 test indicating a relative deficit of heterozygotes in the female patients and a relative excess of heterozygotes in the female control subjects compared with the expected values. In the female patients, those who were of genotype 1/1 were significantly older than those who were in the 1/2+2/2 genotype group (76 [70 to 83] versus 71 [64 to 78] years, P=.023). There was no difference in ages observed in male patients or control subjects or in female control subjects.
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Determinants of Fibrinogen Levels at 3 Months
In all control subjects, fibrinogen levels were associated with age and smoking, which together accounted for 14.7% of the variation in fibrinogen levels. In all patients, fibrinogen levels were associated with age (8.2%), smoking (2.8%), and Bß 448 genotype (4%), accounting for 15% of the variation. In the patients, there was evidence of an interaction between genotype and gender, the interaction term in the model being significantly associated with levels (P=.025). Therefore, considering males and females separately, in male control subjects, levels were associated with age and smoking, together accounting for 33.7% of the variation. Only age (23.5%) was significantly associated with levels in female control subjects. In female patients, age, smoking, and stroke subtype accounted for 16.5% of the variation in levels. In male patients, fibrinogen levels were associated with age and Bß 448 genotype, accounting for 11.2% and 8.4%, respectively. The association of genotype and levels at 3 months was restricted to the male patients (1/1=3.62 [3.35 to 3.90] g/L, 1/2+2/2=4.27 [3.87 to 4.72] g/L, P=.01, with a mean difference of 0.85 (0.75 to 0.96) g/L), as shown in the Figure (panel A). After accounting for the effects of age and smoking on fibrinogen levels, adjusted means were 1/1=3.60 g/L, 1/2 + 2/2=4.29 g/L, P=.004.
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There was no evidence for an interaction between smoking and genotype in any of the groups. The Figure
(panel B) shows the fibrinogen levels of male patients by genotype in smokers and nonsmokers at 3 months.
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Discussion |
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Fibrinogen is an acute-phase reactant, and its levels increase in response to tissue damage, inflammation, and infection.31 Levels are known to be elevated immediately after stroke, and this occurrence has been attributed to the acute-phase response resulting from brain ischemia and necrosis.32 However, in a study investigating fibrinogen and plasma viscosity in three patient groups (stroke, transient ischemic attack, and those at increased stroke risk) compared with normal control subjects, it was found that both fibrinogen and plasma viscosity were raised in all three groups compared with the control subjects.33 These results suggest that fibrinogen levels are increased before stroke. Thus, the initial elevation in fibrinogen levels observed in this study over that at 3 months is likely to be a direct result of tissue damage due to the stroke itself. This hypothesis is supported by the fact that individuals suffering a TACI had higher initial levels of fibrinogen than those with a small-vessel infarction, although this finding was significant only in females. As stroke subtype was unrelated to fibrinogen levels at 3 months, it seems unlikely that fibrinogen levels are a predictor of stroke subtype.
The Framingham and Gothenburg studies1 2 reported high fibrinogen levels to be an independent risk factor for the development of stroke. In the Framingham study,2 which included females, this association with fibrinogen levels and stroke in the 92 events was significant only in males, although the proportion of males to females was not stated. However, the present study supports this finding, as at 3 months there was no difference in levels between female patients and control subjects, but there was a significant difference between male patients and control subjects. This persistent elevation of fibrinogen in the male patients may, however, reflect a low-grade acute-phase response resulting from the presence of underlying atherosclerosis in the vascular wall.
Humphries et al22 have recently demonstrated a gender/genotype interaction between fibrinogen levels and the -455 G/A polymorphism in the 5' flanking region of the ß fibrinogen gene, in which it was reported that the strongest association was found in males. This finding was also reported by de Maat et al23 in a study of the -455 G/A polymorphism and the Bcl I polymorphism of the 3' flanking region of the ß fibrinogen gene and levels in Greenland Inuit. The present study further supports these findings, observing an association between levels and Bß 448 genotype only in the male patients. However, there was no association with genotype and levels in the male control subjects or female patients and control subjects, suggesting that in the male patients, the effect of genotype is being enhanced by other factors affecting levels. The Bß 448 polymorphism has been demonstrated to be in strong linkage disequilibrium with the -455 G/A polymorphism,26 which is itself in complete linkage disequilibrium with the -148 C/T polymorphism in the promoter region of the ß fibrinogen gene.27 The -148 C/T polymorphism lies close to the consensus sequence for the IL6 responsive element and affects binding of nuclear proteins, which may affect the rate of transcription of the Bß fibrinogen gene.34 35 36 It is likely that in relation to fibrinogen levels in male patients in this study, the Bß 448 polymorphism is acting as a marker for these functional promoter polymorphisms.
Fibrinogen levels have been consistently demonstrated to be higher in smokers than nonsmokers.1 13 37 This is likely to result from chronic stimulation of macrophages and subsequent release of IL6.21 IL6 stimulates the binding of positive transcription factors to IL6 responsive elements in the promoter region of each of the three fibrinogen genes, causing a coordinated increase in transcription of the three genes.38 It has been estimated that between 25% and 50% of the increased risk of vascular disease associated with smoking is as a result of increased fibrinogen levels.37 In this study, we found that fibrinogen levels were significantly associated with smoking in patients and control subjects when considered as a whole. However, when considered by gender, smoking was associated with significantly elevated levels of fibrinogen in male control subjects and female patients at 3 months only, but there was a trend toward higher levels in smokers in all groups; this is likely to reflect the smaller size of the groups. A genotype/smoking interaction has also been reported in association with the -455 Bß fibrinogen gene polymorphism.21 22 In the present study, there were significantly more smokers among the male patients than male control subjects, and we investigated the possibility of a smoking/genotype interaction. However, there was no evidence for such an interaction in this population, a similar increase in fibrinogen levels being associated with the 1/2+2/2 group in both smokers and nonsmokers. It is possible that there is an interaction between other unidentified environmental factors and genotype accounting for this difference in association.
There was no significant difference in the genotype distributions of the patients and control subjects when treated as whole groups. On the basis of the observation that there was a gender-specific association between genotype and fibrinogen levels, it appeared more valid to treat the male and female populations separately. It was found that there was a significant difference in the genotype distributions of female patients and control subjects but not of males. The difference in genotype distribution was related to a relative deficit of heterozygotes in the female patients and an excess in the female control subjects. This finding suggests that possession of the 2 allele (lysine) may be protective for females in the development of cerebrovascular disease. It has been demonstrated that the Bcl I polymorphism is associated with the development of peripheral arterial disease by a mechanism unrelated to levels,39 although in this study there was no separate analysis for males and females. It has also recently been reported that polymorphisms of the ß fibrinogen gene are associated with the severity of coronary artery disease in the angiographically characterized patients of the ECTIM study.40 These and the present study suggest that polymorphisms at the fibrinogen gene are involved in the development of vascular disease. Our results suggest that as the Bß 448 fibrinogen polymorphism codes for an amino acid substitution in the Bß polypeptide, it may have a functional role, unrelated to variations in fibrinogen levels, in the development of stroke in females. Although this polymorphism does not occur in a region of the fibrinogen molecule with any characterized functional properties, it cannot be excluded that the amino acid substitution associated with this polymorphism results in an alteration in the structure and therefore the functioning of the fibrinogen molecule in vivo. This possibility requires further investigation. Alternatively, this polymorphism may be in linkage disequilibrium with a functional site elsewhere in the fibrinogen gene locus. However, it would be prudent to consider the possible effects of age and survival on genotype distribution in populations and also the relative limitations of a hospital-based case control study, which may result in skewing of the genotype data. To establish conclusively the role of polymorphisms of the fibrinogen genes in cerebrovascular disease would require a very large prospective study, particularly if females were to be studied as a separate group.
In conclusion, however, this study supports a role for polymorphisms at the fibrinogen gene locus in the development of cerebrovascular disease, although the mechanisms may differ in males and females. It is likely that in the male patients the increased risk is via an increase in fibrinogen levels, which may be influenced by environmental factors unrelated to smoking. In females, the risk may be associated with a functional difference in the fibrinogen molecule, unrelated to fibrinogen levels, resulting in an altered fibrinogen structure, which may result in the formation of a more stable fibrin clot or one that is more resistant to lysis by plasmin. These data suggest that the mechanisms linking fibrinogen and the development of cerebrovascular disease differ in males and females.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was generously supported by the Stroke Association, the United Leeds Teaching Hospitals Special Trustees, and a small project grant from the British Society for Haemostasis and Thrombosis.
Received December 22, 1995; accepted July 10, 1996.
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References |
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 A. Heiat, C. P. Gross, and H. M. Krumholz Representation of the Elderly, Women, and Minorities in Heart Failure Clinical Trials Arch Intern Med, August 12, 2002; 162(15): 1682 - 1688. [Abstract] [Full Text] [PDF]
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 J. B. Braunstein, D. W. Kershner, P. Bray, G. Gerstenblith, S. P. Schulman, W. S. Post, and R. S. Blumenthal Interaction of Hemostatic Genetics With Hormone Therapy : New Insights To Explain Arterial Thrombosis in Postmenopausal Women Chest, March 1, 2002; 121(3): 906 - 920. [Abstract] [Full Text] [PDF]
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 A. J. Catto Genetic aspects of the hemostatic system in cerebrovascular disease Neurology, September 1, 2001; 57(90002): S24 - 30. [Abstract] [Full Text]
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 A. Hassan and H. S. Markus Genetics and ischaemic stroke Brain, September 1, 2000; 123(9): 1784 - 1812. [Abstract] [Full Text] [PDF]
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D. A. Lane and P. J. Grant Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease Blood, March 1, 2000; 95(5): 1517 - 1532. [Full Text] [PDF]
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A. M. Carter, A. J. Catto, J. M. Bamford, and P. J. Grant Association of the Platelet Glycoprotein IIb HPA-3 Polymorphism With Survival After Acute Ischemic Stroke Stroke, December 1, 1999; 30(12): 2606 - 2611. [Abstract] [Full Text] [PDF]
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M. Eriksson, N. Egberg, S. Wamala, K. Orth-Gomer, M. A. Mittleman, and K. Schenck-Gustafsson Relationship Between Plasma Fibrinogen and Coronary Heart Disease in Women Arterioscler Thromb Vasc Biol, January 1, 1999; 19(1): 67 - 72. [Abstract] [Full Text] [PDF]
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J. S. Pankow, A. R. Folsom, M. A. Province, D. C. Rao, R. R. Williams, J. Eckfeldt, and T. A. Sellers Segregation Analysis of Plasminogen Activator Inhibitor-1 and Fibrinogen Levels in the NHLBI Family Heart Study Arterioscler Thromb Vasc Biol, October 1, 1998; 18(10): 1559 - 1567. [Abstract] [Full Text] [PDF]
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A. M. Carter, A. J. Catto, J. M. Bamford, and P. J. Grant Platelet GP IIIa PlA and GP Ib Variable Number Tandem Repeat Polymorphisms and Markers of Platelet Activation in Acute Stroke Arterioscler Thromb Vasc Biol, July 1, 1998; 18(7): 1124 - 1131. [Abstract] [Full Text] [PDF]
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H. Schmidt, R. Schmidt, K. Niederkorn, S. Horner, P. Becsagh, B. Reinhart, M. Schumacher, V. Weinrauch, and G. M. Kostner ß-Fibrinogen Gene Polymorphism (C148->T) Is Associated With Carotid Atherosclerosis : Results of the Austrian Stroke Prevention Study Arterioscler Thromb Vasc Biol, March 1, 1998; 18(3): 487 - 492. [Abstract] [Full Text] [PDF]
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 A. M. Carter, N. Ossei-Gerning, I. J. Wilson, and P. J. Grant Association of the Platelet PlA Polymorphism of Glycoprotein IIb/IIIa and the Fibrinogen Bß 448 Polymorphism With Myocardial Infarction and Extent of Coronary Artery Disease Circulation, September 2, 1997; 96(5): 1424 - 1431. [Abstract] [Full Text]
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