This article has Open Peer Review reports available.
Βeta-fibrinogen gene promoter A −455 allele associated with poor longterm survival among 55–71 years old Caucasian women in Finnish stroke cohort
© Martiskainen et al.; licensee BioMed Central Ltd. 2014
Received: 13 January 2014
Accepted: 17 June 2014
Published: 22 June 2014
Women die of stroke more often than men. After menopause, the incidence of ischemic stroke increases rapidly. Elevated fibrinogen levels and smoking have been associated with an increased risk of stroke. In gene-cluster haplotype analyses, the beta-fibrinogen (FGB) promoter −455 G/A polymorphic locus was most strongly associated with elevated plasma fibrinogen levels. We investigated whether the FGB −455 G/A polymorphism and smoking might interact with sex on longterm survival of acute stroke sufferers.
The Stroke Aging Memory (SAM) cohort comprising 486 consecutive stroke patients (55–85 years, 246 men, 240 women) subjected to clinical and MRI examination was followed over 12.5 years. During this period 347 (71.4%) patients died. The genotypes of the FGB −455 G/A polymorphism were determined by PCR.
The FGB −455 G/A polymorphism genotype distributions were 64.7%, 32.1%, and 3.2% for GG, GA, and AA, respectively. During the follow-up, the FGB −455 A + genotype did not associate with survival, nor was there any genotype-by-smoking interaction on poor outcome in the total study population. However, women aged 55–71 years who carried the FGB −455 A-allele showed worse survival regardless of smoking status compared to non-smoking FGB −455 GG homozygotes (non-smokers, crude HR = 5.21, 95% CI: 1.38-19.7; smokers, crude HR = 7.03, 95% CI: 1.81-27.3). This association persisted in adjusted analyses. No such association was observed for women in the oldest age-group, nor among men.
The A + genotype of the FGB −455 G/A polymorphism associated with poor survival among 55–71 years old Caucasian women in the Finnish stroke cohort.
Cardiovascular and cerebrovascular diseases are major causes of death in industrialized countries, and stroke is the leading cause of adult disability in the developed world [1, 2]. While combined death rates and hospitalization periods of cardiovascular diseases due to myocardial infarction have decreased greatly, the numbers related to stroke have decreased only slightly. In addition to family history and lifestyle factors, gene-environment interactions seem to determine the development and manifestation of cardio- and cerebrovascular diseases through inflammatory and prothrombotic processes [3–7].
Despite a lower incidence of stroke over one’s lifetime, women are twice as likely to die from stroke as men and during menopause the incidence of ischemic stroke increases rapidly [8–10]. Postmenopausal women suffer more severe and fatal strokes indicating the presence of possible unknown sex-specific and genetic factors . Possible approaches to the search for genetic factors of stroke are genome-wide association studies (GWAS) and candidate gene studies. While GWAS have uncovered numerous associations with metabolic endpoints, it has been more challenging to discover associations with complex diseases in spite of the formation of large consortia . An alternative to GWAS is the investigation of candidate genes based on knowledge of risk factors or the pathophysiology of the disease.
Fibrinogen is a dimeric 340 kDa acute phase glycoprotein synthesized by the liver. It consists of three polypeptides Aα, Bβ and γ coded by the alpha (FGA), beta (FGB) and gamma (FGG) genes, respectively . Fibrinogen is an important component of the coagulation cascade and a major determinant of blood viscosity and platelet aggregation. It modulates endothelial function and promotes smooth muscle cell proliferation and migration [4, 7]. Smoking increases blood fibrinogen concentration and is a significant risk factor for stroke [14–16]. Recently, obesity has been associated with elevated fibrinogen and CRP levels .
In the SAM cohort, we have previously found a genotype-by-smoking interaction between the A-allele of the FGB −455 G/A polymorphism and recurrent lacunar infarcts, as well as an interaction between smoking and the blood platelet fibrinogen receptor (GpIIb/IIIa) PlA2 allele as a risk factor for lacunar cerebral infarction [18, 19]. In haplotype analyses covering the entire FGB-gene, the FGB −455 G/A polymorphism (rs1800790) shows the strongest association with blood fibrinogen levels, although a direct relationship with atherothrombotic disease is lacking [6, 20–25].
The A + genotype of the FGB −455 G/A polymorphism acts as an individual risk factor for coronary artery disease (CAD), acute coronary syndromes (ACS), peripheral arterial disease (PAD) and stroke [7, 14, 26–30]. In the present study our hypothesis is that the FGB −455 G/A polymorphism might interact with smoking and interfere sex specific longterm survival after stroke.
The Helsinki Stroke Aging Memory (SAM) cohort comprises of a consecutive series of all Finnish (Caucasian) patients with suspected stroke admitted to Helsinki University Central Hospital (n = 1622) between the 1st of December 1993 and the 30th of March 1995. A total of 486 (246 men, 240 women) living patients aged 55 to 85 years (mean age 71.3 years) were recruited for the study 3 months after experiencing an ischemic stroke - more detailed descriptions of the study series and methods have been described elsewhere [17, 18, 31, 32].
General clinical assessment
Main characteristics of 371 patients in the SAM cohort with survival and genotype data according to -455G/A genotypes
FGB −455 G/A genotype
G/G (n = 240)
G/A + A/A (n = 131)
Age (mean, SD), y
CRP >10 mg/L, %
Mean fs-Chol (SD)
Mean fs-Chol-HDL (SD)
Subtypes of ischemic stroke
Large artery, %
Carotid artery stenosis, %
Atrial fibrillation, %
DNA was separated from frozen blood samples according to standard procedures. The genotypes of the FGB −455 G/A polymorphism were detected by polymerase chain reaction (PCR) and restriction enzyme digestion, followed by poly-acrylamide gel electrophoresis. Primer sequences and the PCR protocol have been previously described in detail .
Data was analysed using SPSS/WIN (version 20.0, SPSS Inc.) software. The number of A/A homozygotes of the FGB −455 G/A polymorphism was small among SAM cohort patients and therefore A/A homozygotes and G/A heterozygotes were grouped together to form the A + genotype variable of the of the FGB −455 G/A polymorphism. The data was analysed as whole and in subgroups that were formed using sex and the mean age (71 years) to divide the data into age groups (55–71 and 72–85 years old) in intention to study the sex and age dependence. To study the association between risk factors including FGB −455 G/A A + genotype and survival we first analysed the data by Kaplan-Meier (log rank) survival analysis and graphical approach was used in verification that the proportional hazards assumption was met. Subsequently, the Cox regression proportional hazards model was used to study the association between FGB −455 G/A A + genotype and survival. First we obtained crude hazard ratios (HRs) and confidence intervals (CIs) and then we used multivariate Cox regression analysis in further statistical testing of genotype-survival association with age, history of previous arrhythmias, atrial fibrillation (AF), carotid stenosis (CS), elevated CRP (>10 mg/l), diabetes, hypercholesterolemia, hypertension, hypertriglyceridemia, history of myocardial infarction (MI), sex and smoking pooled into forced and forward stepwise likelihood ratio (LR) models. To further adjust the analyses we stratified Cox regression models (forced and forward stepwise) with each modifier (history of previous arrhythmias, AF, CS, elevated CRP (>10 mg/l), diabetes, hypercholesterolemia, hypertension, hypertriglyceridemia, history of MI and smoking) separately and used age and sex as confounders. The data concerning the history of arrhythmias, AF, CS, diabetes, hypertension, hypercholesterolemia and hypertriglyceridemia was missing in 118 (24.3%) of patients. Furthermore, based on Little’s MCAR (missing completely at random) test (p < 0.05) we concluded that the data was not missing completely at random. Overall summary of missing values showed that each case with missing values had, on average, missing values on roughly 3.37 of the 10 variables suggesting that listwise deletion would lose much of the information in the data. The data missingness pattern was nonmonotone and the random number generator was used to simulate missing values for each observation that were imputed with fully conditional specification (FCS) Markov Chain – Monte Carlo (MCMC) method assuming multivariate normality and five imputations was suitable in graphic check for FCS convergence. Then we analyzed the complete data with Cox regression model to check differences in survival in total population and in subgroups with pooled parameter estimates and we also checked of the variation in the regression coefficient estimates from imputation to imputation, and against the original data. The results were not altered after imputations. Survival analyses for LAI or LVI subgroups, stroke types (TOAST) and specific causes of death were also completed. According to power calculations our study population has the power to show hazard ratios >2.5 to be statistically significant with 0.80 probability (power) when the Type I error probability is 0.05 .
Prevalence of FGB −455 G/A alleles
There were 371 patients with the FGB −455 G/A polymorphism genotype and clinical data available. The study population comprised 50.7% (186) male patients. The mean age was 71.0 years (SD ± 7.81) and the data was normally distributed. There were 186 smokers (50.1%) in the study population (84.9% men and 15.1% women). Allele distributions were in Hardy-Weinberg equilibrium (p = 0.74). Genotype distributions were 64.7% for GG, 32.1% for GA, and 3.2% for AA. These frequencies closely correspond to the population frequencies among whites; in the ECTIM study, the allele frequencies were 65.9%, 29.1%, and 4.9%, respectively . The main demographic parameters are represented in Table 1.
Causes of death
Causes of death according to age group (55–71 and 72–85 years) and sex during longterm post stroke follow-up in the SAM cohort
Cause of death
n = 74
n = 188
n = 53
n = 79
n = 21
n = 109
As expected, age was associated (p < 0.001) with survival in Kaplan-Meier log rank analyses. In the multivariate Cox regression model, age (HR = 1.08, 95% CI: 1.06-2.00, p = 0.005) and diabetes (HR = 1.39, 95% CI: 1.05-1.83, p = 0.03) associated significantly with poor survival. However, significant association between diabetes and risk of cardiac death (HR = 1.59, 95% CI: 0.97-2.59) was not observed in multivariate Cox regression analysis. Smoking had no statistically significant (p = 0.06) effect on survival in the Kaplan-Meier log rank analysis that was also observed in the multivariate Cox Regression model (HR = 1.26, 95% CI: 0.97-1.65) and it was not dependent on sex. In contrast, hypercholesterolemia or elevated cholesterol levels known to increase risk for further cardiovascular events, but paradoxically associates with lower mortality in old age had a positive (HR = 0.65, 95% CI: 0.43-0.99, p = 0.05) impact on longterm post stroke survival in Cox regression model .
Cox regression analysis of the association of the FGB −455 G/A genotype-by-smoking interaction term with longterm survival (all cause death endpoint) among patients with ischemic stroke of the SAM cohort (HRs and CIs are represented as crude)
FGB −455 G/A carrier and smoking status
HR 95% CI
HR 95% CI
HR 95% CI
HR 95% CI
HR 95% CI
HR 95% CI
HR 95% CI
The A + genotype of the FGB −455 G/A polymorphism was associated with poor post stroke survival among 55–71 years old postmenopausal women of the Stroke Aging Memory (SAM) study cohort, representing a consecutive series of all Finnish (Caucasian) patients with suspected stroke admitted to Helsinki University Central Hospital during 16 months in 1993–1995. This association was not observed in older women of the cohort or among men.
In our study, the significant association between FGB −455 G/A polymorphism and survival in total study population was not observed. Pruissen et al. previously studied the impact of FGB −455 G/A polymorphism and other prothrombotic polymorphisms on composite outcome events after cerebral ischemia of arterial origin . They found that FGB −455 G/A polymorphism did not associate with survival that is in line with our results when the whole series was studied without sex or age dependences. The lack of significant association between the A + genotype of the FGB −455 G/A polymorphism and poor survival among older patients (72–85 years) may be explained by the burden of other illnesses and old age predisposing to poor outcome. However, our finding on the association of FGB −455 G/A A-allele with poor survival is restricted only to postmenopausal women of age 55 to 71 years for we had no premenopausal women included into the SAM cohort. In addition, we found that 34.6% of women and 27.3% of men had ischemic brain insults as the cause of death that supports the concept that women are at greater risk of stroke after menopause (Table 2). However, we did not observe any genotype-by-smoking interaction with causes of death, although smoking is known to increase fibrinogen levels.
During menopause, the protective effect of estrogen against stroke and cardiovascular diseases reduces and hormone replacement therapy (HRT) used to treat the symptoms of menopause acts as a risk factor for stroke [38–40]. Based on the data of The Finnish National Health Institute, 32.0% of women aged 55–70 years and 11.0% of women aged 71–85 years used HRT during the year 1996. Furthermore, 40.9% of women aged 55–64 years used HRT in Finland during the year 1999 . The exact statistics concerning HRT use in the Helsinki region during the early 1990’s could not be obtained as national computer-based databases of pharmaceutical store sales were gradually taken into use in Finland only in the late 1990’s. As HRT is exclusively used in the group of 55–70 year old women, in contrast to those at the age of 71–85 we may speculate that our results might be partly explained by a synergy between the FGB −455 A + genotype, smoking and HRT. On the contrary, transdermal estradiol therapy may have antiatherosclerotic effects in postmenopausal women by improving vascular atherosclerosis . Matsui S et al. have found that HRT regimen using oral ultra-low-dose estradiol and dydrogesterone has an improving effect on arterial stiffness and insulin resistance in 28 postmenopausal women . As we do not have data on medication history that is an important limitation of our study, the potential effect of HRT on stroke risk or survival could not be evaluated. Furthermore, HRT may act as a strong confounding factor and have an impact on the results.
The SAM cohort with study subpopulations are limited in size and the main finding of positive association of FGB −455 G/A A-allele with poor survival is based on a subgroup of only 21 women aged 55–71 years old that complicates the interpretation of the results. However, this association without the smoking status dependence was already observed in 55–71 years old patients of the SAM cohort (Table 3). In addition, the SAM cohort is too small to allow the detailed analysis of all fibrinogen haplotypes and their impact on survival. One limitation in our study is that the blood or plasma fibrinogen levels were not determined. However the A-allele of the FGB −455 G/A polymorphism has been shown to associate with elevated fibrinogen levels and possess functional properties .
Overweight/obese women without clustering of cardiometabolic risk factors possess abnormal levels of inflammatory markers including CRP and fibrinogen suggesting that obesity represents a chronic inflammatory state . We could not assess the effect of obesity on survival. In our cohort adjustment for elevated CRP (>10 mg/L) value as a marker of inflammation caused a significant increase in the point HR estimates addressing the significant association of FGB −455 G/A A + genotype towards poor survival. However, the CIs widened substantially that reflects the small number of patients in this subgroup analysis (Figure 2). Therefore the interaction between FGB −455 G/A polymorphism and elevated CRP remains unclear. In recent study of Ock SY et al. the elevated plasma CRP concentration were discussed to be a reliable surrogate marker for predicting carotid atherosclerosis severity in patients with AF, and that CRP concentration may be related to an increased risk of ischemic stroke . In addition, CRP activity has been positively correlated with plaque instability as well as intima to media wall thickness of coronary arteries and the common carotid artery [46, 47]. Concerning these, ischemic stroke is a complex trait with polygenic and multifactorial inheritance with environmental triggers [48, 49]. Gene-environment-life style interactions influence the risk for stroke in an individual, and based on our findings these may modify the survival from stroke.
Misclassification of the exposure is unlikely since medical history and risk factor data were derived from administrative hospital data and genotyping was made in the accredited laboratory. The stroke diagnosis and classification were based on MRI and patients were assessed by a senior neurologist that diminishes misclassification of the outcome. In addition, the possibility of a selection bias may underestimate the proportion of women who died before hospital assessment at 3 months. Furthermore, the initiation of antithrombotic, antihypertensive and lipid treatments poststroke may attenuate the effect of genetic factors on survival. Limitations of the cohort are also discussed in previous publication by Oksala N et al. .
Taking in account the limitations of the present study, our study highlights the contribution of the A + genotype of the FGB −455 G/A polymorphism towards poor poststroke survival among 55–71 years old Caucasian women even after adjustment for arrhythmias, AF, CS, CRP, hypercholesterolemia, hypertension, hypertriglyceridemia, and history of MI with age and sex as confounding factors. This association was not observed in older women or among men. The SAM cohort does not comprise stroke patients under 55 years old and the association of FGB −455 G/A polymorphism with poor survival could not be assessed in premenopausal women. Furthermore, we found a substantial interaction in the adjusted risk of death attributable to FGB −455 G/A A + genotype and elevated CRP that warrants the further investigation of possible gene-environment-life-style interactions.
This study has been supported by grants from the Tampere University Hospital Research Foundation, the Medical Research Fund of Tampere University Hospital, the Pirkanmaa Regional Fund of the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research.
- Saver J, Tamburi T: Genetics of cerebrovascular disease. Neurogenetics. Edited by: Stefan MP. 2000, Oxford: Oxford University Press, 403-431.Google Scholar
- World Health Organization: World health statistics. 2009, http://www.who.int/gho/publications/world_health_statistics/EN_WHS08_Full.pdf,Google Scholar
- Ajjan R, Grant PJ: Coagulation and atherothrombotic disease. Atherosclerosis. 2006, 186: 240-259.View ArticlePubMedGoogle Scholar
- Danesh J, Lewington S, Thompson SG, Lowe GD, Collins R, Kostis JB, Wilson AC, Folsom AR, Wu K, Benderly M, Goldbourt U, Willeit J, Kiechl S, Yarnell JW, Sweetnam PM, Elwood PC, Cushman M, Psaty BM, Tracy RP, Tybjaerg-Hansen A, Haverkate F, de Maat MP, Fowkes FG, Lee AJ, Smith FB, Salomaa V, Harald K, Rasi R, Vahtera E, Fibrinogen Studies Collaboration, et al: Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA. 2005, 294: 1799-1809.PubMedGoogle Scholar
- Mosesson MW: Fibrinogen and fibrin structure and functions. J Thromb Haemost. 2005, 3: 1894-1904.View ArticlePubMedGoogle Scholar
- Weng X, Cloutier G, Genest J: Contribution of the -455G/A polymorphism at the beta-fibrinogen gene to erythrocyte aggregation in patients with coronary artery disease. Thromb Haemost. 1999, 82: 1406-1411.PubMedGoogle Scholar
- Voetsch B, Loscalzo J: Genetic determinants of arterial thrombosis. Arterioscler Thromb Vasc Biol. 2004, 24: 216-229.View ArticlePubMedGoogle Scholar
- Bonita R: Epidemiology of stroke. Lancet. 1992, 39: 342-344.View ArticleGoogle Scholar
- Eaker ED, Chesebro JH, Sacks FM, Wenger NK, Whisnant JP, Winston M: Cardiovascular disease in women. Circulation. 1993, 88: 1999-2009.View ArticlePubMedGoogle Scholar
- Sudlow CL, Warlow CP: Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke. 1997, 28: 491-499.View ArticlePubMedGoogle Scholar
- Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T: American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006, 113: 85-151.View ArticleGoogle Scholar
- Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA: Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci. 2009, 106: 9362-9367.View ArticlePubMedPubMed CentralGoogle Scholar
- Kant JA, Fornace AJ, Saxe D, Simon MI, McBride OW, Crabtree GR: Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion. Proc Natl Acad Sci U S A. 1985, 82: 2344-2348.View ArticlePubMedPubMed CentralGoogle Scholar
- Thomas AE, Green FR, Humphries SE: Association of genetic variation at the beta-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.View ArticlePubMedGoogle Scholar
- Mannami T, Iso H, Baba S, Sasaki S, Okada K, Konishi M, Tsugane S, Japan Public Health Center-Based Prospective Study on Cancer and Cardiovascular Disease Group: Cigarette smoking and risk of stroke and its subtypes among middle-aged Japanese men and women: the JPHC Study Cohort I. Stroke. 2004, 35: 1248-1253.View ArticlePubMedGoogle Scholar
- Ueshima H, Choudhury SR, Okayama A, Hayakawa T, Kita Y, Kadowaki T, Okamura T, Minowa M, Iimura O: Cigarette smoking as a risk factor for stroke death in Japan: NIPPON DATA80. Stroke. 2004, 35: 1836-1841.View ArticlePubMedGoogle Scholar
- Wildman RP, Kaplan R, Manson JE, Rajkovic A, Connelly SA, Mackey RH, Tinker LF, Curb JD, Eaton CB, Wassertheil-Smoller S: Body size phenotypes and inflammation in the Women’s Health Initiative Observational Study. Obesity (Silver Spring). 2011, 19 (suppl7): 1482-1491.View ArticleGoogle Scholar
- Martiskainen M, Pohjasvaara T, Mikkelsson J, Mantyla R, Kunnas T, Laippala P, Ilveskoski E, Kaste M, Karhunen PJ, Erkinjuntti T: Fibrinogen gene promoter −455 A allele as a risk factor for lacunar stroke. Stroke. 2003, 34: 886-891.View ArticlePubMedGoogle Scholar
- Oksala NK, Heikkinen M, Mikkelsson J, Pohjasvaara T, Kaste M, Erkinjuntti T, Karhunen P: Smoking and the platelet fibrinogen receptor glycoprotein IIb/IIIA PlA1/A2 polymorphism interact in the risk of lacunar stroke and midterm survival. Stroke. 2007, 38: 50-55.View ArticlePubMedGoogle Scholar
- van ’t Hooft FM, von Bahr SJ, Silveira A, Iliadou A, Eriksson P, Hamsten A: Two common, functional polymorphisms in the promoter region of the beta-fibrinogen gene contribute to regulation of plasma fibrinogen concentration. Arterioscler Thromb Vasc Biol. 1999, 19: 3063-3070.View ArticlePubMedGoogle Scholar
- Carty CL, Cushman M, Jones D, Lange LA, Hindorff LA, Rice K, Jenny NS, Durda JP, Walston J, Carlson CS, Nickerson D, Tracy RP, Reiner AP: Associations between common fibrinogen gene polymorphisms and cardiovascular disease in older adults. The Cardiovascular Health Study. Thromb Haemost. 2008, 99: 388-395.PubMedGoogle Scholar
- Reiner AP, Carty CL, Carlson CS, Wan JY, Rieder MJ, Smith JD, Rice K, Fornage M, Jaquish CE, Williams OD, Tracy RP, Lewis CE, Siscovick DS, Boerwinkle E, Nickerson DA: Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study. J Thromb Haemost. 2006, 4: 1279-1287.View ArticlePubMedGoogle Scholar
- Jacquemin B, Antoniades C, Nyberg F, Plana E, Muller M, Greven S, Salomaa V, Sunyer J, Bellander T, Chalamandaris AG, Pistelli R, Koenig W, Peters A: Common genetic polymorphisms and haplotypes of fibrinogen alpha, beta, and gamma chains affect fibrinogen levels and the response to proinflammatory stimulation in myocardial infarction survivors: the AIRGENE study. J Am Coll Cardiol. 2008, 52: 941-952.View ArticlePubMedGoogle Scholar
- Mannila MN, Silveira A, Hawe E, Eriksson P, Aillaud MF, Juhan-Vague I, Yudkin J, Margaglione M, di Minno G, Mussoni L, Tremoli E, Humphries S, Hamsten A, HIFMECH Study Group: Plasma fibrinogen concentration predicts the risk of myocardial infarction differently in various parts of Europe: effects of beta-fibrinogen genotype and environmental factors The HIFMECH Study. Thromb Haemost. 2004, 92: 1240-1249.PubMedGoogle Scholar
- Koch W, Hoppmann P, Biele J, Mueller JC, Schomig A, Kastrati A: Fibrinogen genes and myocardial infarction: a haplotype analysis. Arterioscler Thromb Vasc Biol. 2008, 28: 758-763.View ArticlePubMedGoogle Scholar
- de Maat MP, Kastelein JJ, Jukema JW, Zwinderman AH, Jansen H, Groenemeier B, Bruschke AV, Kluft C: 455G/A polymorphism of the beta-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.View ArticlePubMedGoogle Scholar
- Behague I, Poirier O, Nicaud V, Evans A, Arveiler D, Luc G, Cambou JP, Scarabin PY, Bara L, Green F, Cambien F: Beta 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.View ArticlePubMedGoogle Scholar
- Rothwell PM, Howard SC, Power DA, Gutnikov SA, Algra A, van Gijn J, Clark TG, Murphy MF, Warlow CP: Fibrinogen concentration and risk of ischemic stroke and acute coronary events in 5113 patients with transient ischemic attack and minor ischemic stroke. Stroke. 2004, 35: 2300-2305.View ArticlePubMedGoogle Scholar
- Green FR: Fibrinogen polymorphisms and atherothrombotic disease. Ann N Y Acad Sci. 2001, 936: 549-559.View ArticlePubMedGoogle Scholar
- Xu X, Li J, Sheng W, Liu L: Meta-analysis of genetic studies from Journals Published in China of ischemic stroke in the Han Chinese Population. Cerebrovasc Dis. 2008, 26: 48-62.View ArticlePubMedGoogle Scholar
- Pohjasvaara T, Erkinjuntti T, Vataja R, Kaste M: Comparison of stroke features and disability in daily life in patients with ischemic stroke aged 55 to 70 and 71 to 85 years. Stroke. 1997, 28: 729-735.View ArticlePubMedGoogle Scholar
- Melkas S, Oksala NK, Jokinen H, Pohjasvaara T, Vataja R, Oksala A, Kaste M, Karhunen PJ, Erkinjuntti T: Post-stroke dementia predicts poor survival in long-term follow-up: influence of prestroke cognitive decline and previous stroke. J Neurol Neurosurg Psychiatry. 2009, 80: 865-870.View ArticlePubMedGoogle Scholar
- Mantyla R, Aronen HJ, Salonen O, Pohjasvaara T, Korpelainen M, Peltonen T, Standertskjöld-Nordenstam CG, Kaste M, Erkinjuntti T: Magnetic resonance imaging white matter hyperintensities and mechanism of ischemic stroke. Stroke. 1999, 30: 2053-2058.View ArticlePubMedGoogle Scholar
- Humphries SE, Ye S, Talmud P, Bara L, Wilhelmsen L, Tiret L: European Atherosclerosis Research Study: genotype at the fibrinogen locus (G-455-A beta-gene) is associated with differences in plasma fibrinogen levels in young men and women from different regions in Europe. Evidence for sex-genotype-environment interaction. Arterioscler Thromb Vasc Biol. 1995, 15: 96-104.View ArticlePubMedGoogle Scholar
- Power and Sample Size Calculation: http://biostat.mc.vanderbilt.edu/wiki/Main/PowerSampleSize,
- Tuikkala P, Hartikainen S, Korhonen MJ, Lavikainen P, Kettunen R, Sulkava R, Enlund H: Serum total cholesterol levels and all-cause mortality in a home-dwelling elderly population: a six-year follow-up. Scand J Prim Health Care. 2010, 28: 121-127. doi:10.3109/02813432.2010.487371View ArticlePubMedPubMed CentralGoogle Scholar
- Pruissen DM, Rosendaal FR, Frijns CJ, Kappelle LJ, Vos HL, Algra A, Smart Study Group: Prothrombotic gene variation and new vascular events after cerebral ischemia of arterial origin. J Thromb Haemost. 2008, 6: 1639-1644.View ArticlePubMedGoogle Scholar
- Bushnell CD, Hurn P, Colton C, Miller VM, del Zoppo G, Elkind MS, Stern B, Herrington D, Ford-Lynch G, Gorelick P, James A, Brown CM, Choi E, Bray P, Newby LK, Goldstein LB, Simpkins J: Advancing the study of stroke in women: summary and recommendations for future research from an NINDS-Sponsored Multidisciplinary Working Group. Stroke. 2006, 37: 2387-2399.View ArticlePubMedGoogle Scholar
- Carswell HV, Macrae IM, Farr TD: Complexities of oestrogen in stroke. Clin Sci (Lond). 2009, 118: 375-389.View ArticleGoogle Scholar
- Bath PM, Gray LJ: Association between hormone replacement therapy and subsequent stroke: a meta-analysis. BMJ. 2005, 12: 330-342.Google Scholar
- Health Behaviour and Health among Finnish Adult Population, Spring 1999. [http://urn.fi/URN:ISBN:951-740-153-1]
- Sumino H, Murakami M: Investigation of atherosclerosis in postmenopausal women: alteration of atherosclerosis-associated factors and vascular atherosclerosis by oral and transdermal estrogen replacement. Rinsho Byori. 2013, 61 (3): 256-262.PubMedGoogle Scholar
- Matsui S, Yasui T, Tani A, Kato T, Uemura H, Kuwahara A, Matsuzaki T, Arisawa K, Irahara M: Effect of ultra-low-dose estradiol and dydrogesterone on arterial stiffness in postmenopausal women. Climacteric. 2014, 17 (2): 191-196.View ArticlePubMedGoogle Scholar
- Brown ET, Fuller GM: Detection of a complex that associates with the Bbeta fibrinogen G-455-A polymorphism. Blood. 1998, 92: 3286-3293.PubMedGoogle Scholar
- Ock SY, Cho KI, Kim HJ, Lee NY, Kim EJ, Kim NK, Lee WH, Yeo GE, Heo JJ, Han YJ, Cha TJ: The impacts of C-reactive protein and atrial fibrillation on carotid atherosclerosis and ischemic stroke in patients with suspected ischemic cerebrovascular disease: a single-center retrospective observational cohort study. Korean Circ J. 2013, 43: 796-803.View ArticlePubMedPubMed CentralGoogle Scholar
- Lombardo A, Biasucci LM, Lanza GA, Coli S, Silvestri P, Cianflone D, Liuzzo G, Burzotta F, Crea F, Maseri A: Inflammation as a possible link between coronary and carotid plaque instability. Circulation. 2004, 109: 3158-3163.View ArticlePubMedGoogle Scholar
- Alvarez Garcia B, Ruiz C, Chacon P, Sabin JA, Matas M: High-sensitivity C-reactive protein in high-grade carotid stenosis: risk marker for unstable carotid plaque. J Vasc Surg. 2003, 38: 1018-1024.View ArticlePubMedGoogle Scholar
- Bersano A, Ballabio E, Bresolin N, Candelise L: Genetic polymorphisms for the study of multifactorial stroke. Hum Mutat. 2008, 29: 776-795.View ArticlePubMedGoogle Scholar
- Hassan A, Markus HS: Genetics and ischaemic stroke. Brain. 2000, 123: 1784-1812.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://0-www.biomedcentral.com.brum.beds.ac.uk/1471-2377/14/137/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.