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

BACKGROUND: Previous genotype-phenotype association studies of fibrinogen have been limited by incomplete knowledge of genomic sequence variation within and between major ethnic groups in FGB, FGA, and FGG. METHODS: We characterized the linkage disequilibrium patterns and haplotype structure across the human fibrinogen gene locus in European- and African-American populations. We analyzed the association between common polymorphisms in the fibrinogen genes and circulating levels of both 'functional' fibrinogen (measured by the Clauss clotting rate method) and total fibrinogen (measured by immunonephelometry) in a large, multi-center, bi-racial cohort of young US adults. RESULTS: A common haplotype tagged by the A minor allele of the well-studied FGB-455 G/A promoter polymorphism (FGB 1437) was confirmed to be strongly associated with increased plasma fibrinogen levels. Two non-coding variants specific to African-American chromosomes, FGA 3845 A and FGG 5729 G, were each associated with lower plasma fibrinogen levels. In European-Americans, a common haplotype tagged by FGA Thr312Ala and several other variant alleles across the fibrinogen gene locus was strongly associated with decreased fibrinogen levels as measured by functional assay, but not by immunoassay. Overall, common polymorphisms within the three fibrinogen genes explain < 2% of the variability in plasma fibrinogen concentration. CONCLUSIONS: In young adults, fibrinogen multi-locus genotypes are associated with plasma fibrinogen levels. The specific single nucleotide polymorphism and haplotype patterns for these associations differ according to population and also according to phenotypic assay. It is likely that a substantial proportion of the heritable component of plasma fibrinogen concentration is due to genetic variation outside the three fibrinogen genes.     

Fibrinogen gene variation and ischemic stroke

Summary.  Background : Plasma fibrinogen level and fibrin clot structure are heritable traits that may be of importance in the pathogenesis of ischemic stroke. Objectives : To investigate associations between variation in the fibrinogen gamma (FGG), alpha (FGA) and beta (FGB) genes, fibrinogen level, and ischemic stroke. Methods : The Sahlgrenska Academy Study on Ischemic Stroke comprises 600 cases and 600 matched population controls. Stroke subtypes were defined according to TOAST criteria. Plasma fibrinogen level was measured by an automated clot-rate assay. Eight tagging single nucleotide polymorphisms (SNPs) were selected to capture genetic variation in the FGA, FGG, and FGB genes. Results:  Plasma fibrinogen was independently associated with overall ischemic stroke and all subtypes, both in the acute stage ( P  < 0.001) and at three-month follow-up ( P  < 0.05). SNPs belonged to two haplotype blocks, one containing the FGB gene and the other the FGG and FGA genes. FGB haplotypes were associated with fibrinogen level ( P  < 0.01), but not with ischemic stroke. In contrast, FGG/FGA haplotypes showed independent association to ischemic stroke but not to fibrinogen level. In an additive model with the most common FGG/FGA haplotype (A1) as reference, the adjusted odds ratios of ischemic stroke were 1.4 [95% confidence interval (95% CI) 1.1–1.8], P  < 0.01, 1.4 (95% CI 1.0–1.8), P  < 0.05, and 1.5 (95% CI 1.0–2.1), P  < 0.05 for the A2, A3, and A4 FGG/FGA haplotypes, respectively. Conclusion:  FGG/FGA haplotypes show association to ischemic stroke. This association is independent of fibrinogen level, thus suggesting that the association between ischemic stroke and variation at the FGG/FGA genes is mediated by qualitative rather than quantitative effects on fibrin(ogen).     

Elevated plasma fibrinogen γ'' concentration is associated with myocardial infarction: effects of variation in fibrinogen genes and environmental factors

BACKGROUND: Fibrinogen gamma', a fibrinogen gamma-chain variant generated via alternative mRNA processing, has been associated with susceptibility to thrombotic disease. OBJECTIVE: The present case-control study searched for potential determinants of the plasma fibrinogen gamma' concentration and examined the relationship between this variant and risk of myocardial infarction (MI). PATIENTS AND METHODS: The Stockholm Coronary Artery Risk Factor study, comprising 387 postinfarction patients and 387 healthy individuals, was employed. The fibrinogen gamma (FGG) 9340T > C [rs1049636], fibrinogen alpha (FGA) 2224G > A [rs2070011] and fibrinogen beta (FGB) 1038G > A [rs1800791] polymorphisms were determined. The plasma fibrinogen gamma' concentration was measured by enzyme-linked immunosorbent assay. The multifactor dimensionality reduction method was used for interaction analyses on risk of MI. RESULTS: The FGG 9340T > C and FGA 2224G > A polymorphisms, total plasma concentrations of fibrinogen, insulin and high-density lipoprotein, and gender appeared to be independent determinants of plasma fibrinogen gamma' concentration in patients, and the corresponding determinants in controls included FGG 9340T > C and FGA 2224G > A polymorphisms and plasma fibrinogen concentration. An elevated plasma fibrinogen gamma' concentration proved to be an independent predictor of MI [adjusted odds ratio (OR) (95% CI): 1.24 (1.01, 1.52)]. The plasma fibrinogen gamma' concentration was involved in a high-order interaction with total plasma fibrinogen and the FGG 9340T > C and FGA 2224G > A polymorphisms, associated with a further increased risk of MI [OR (95% CI): 3.22 (2.35, 4.39)]. CONCLUSIONS: Plasma fibrinogen gamma' concentration influences the risk of MI, and this relationship seems to be strengthened by the presence of an elevated total plasma fibrinogen concentration and the FGG 9340T and FGA 2224G alleles.     

Assessing the contribution of fibrinogen in predicting risk of death in men with peripheral arterial disease

Summary.  Background:  Although fibrinogen is known to be an independent population-level risk factor for cardiovascular disease in healthy individuals, less is known about its value for individual-level risk prediction. Objectives:  To assess the independent contribution of plasma fibrinogen to risk prediction in men with peripheral arterial disease. Patients and methods:  We used data from the 785 men randomized to placebo in the Lower Extremity Arterial Disease Event Reduction (LEADER) trial. Men were followed at 6-monthly intervals up to 3 years, during which 116 patients died. Multivariable standard and pooled logistic regression were used to model odds of death in the next 3 years or in a 6-month interval. The c-statistic and predictiveness curves were used to assess improvement in predictive ability. Results:  Fibrinogen measured at baseline was an independent predictor of all-cause mortality risk (adjusted odds ratio [OR] 1.44, 95% confidence interval [CI] 1.02–1.94, for a 1 g L⁻¹ increase). Adding baseline fibrinogen to a set of other risk factors did not, however, substantially improve predictive ability. Similarly, fibrinogen measured at the start of a 6-month interval was independently associated with odds of death in the next 6 months (adjusted OR 1.65; 95% CI  0.96–2.73). Again, predictiveness curves with and without fibrinogen did not substantially differ, although the c-statistic increased by 0.011. Conclusions:  Although fibrinogen was independently associated with both 6-month and 3-year mortality risk, individual-level risk prediction was not substantially improved by including fibrinogen in risk models.     

Tissue factor gene polymorphisms and haplotypes and the risk of ischemic vascular events: four studies and a meta-analysis

Summary  Objective : The exposure of tissue factor (TF) to blood flow is the initial step in the coagulation process and plays an important role in thrombogenesis. We investigated the role of genetic polymorphisms and haplotypes of the TF gene in the risk of ischemic vascular disease. Methods : Four hundred and twenty-two Italian patients with juvenile myocardial infarction (MI) and 434 controls, 808 US cases with MI and 1005 controls, 267 Italian cases with juvenile ischemic stroke and 209 controls and 148 German cases with juvenile ischemic stroke and 191 controls were studied. rs1361600 , rs3917629 (rs3354 in the US population), rs1324214 and rs3917639 Tag single nucleotide polymorphisms were genotyped. Additionally, a meta-analysis of all previous studies on TF loci and the risk of ischemic coronary disease (ICD) was performed. Results : After multivariable analysis none of the SNPs, major SNP haplotypes or haplotype-pairs showed any consistent association with MI. Pooled meta-analysis of six studies also suggested that TF polymorphisms are not associated with CHD. A significant, independent association between SNP rs1324214 (C/T) and juvenile stroke was found in Italian and German populations (OR for TT homozygotes = 0.47, 95% CI 0.24–0.92, in combined analysis). Pooled analysis also showed a significant association for haplotype H3 (OR = 0.76, 95% CI 0.57–1.00) and haplotype-pair H3–H3 (OR = 0.43, 95% CI 0.20–0.92). Conclusions : TF genetic variations were associated with the risk of ischemic stroke at young age, but did not affect ischemic coronary disease.     

ABO genotype and risk of thrombotic events and hemorrhagic stroke

Summary. Background: The non‐O alleles of the ABO genotype have been associated with an increased risk of thrombosis. Risk associated with the specific A¹, A² or B alleles is not well defined. Objectives: To examine the association of the ABO genotype with myocardial infarction (MI), ischemic stroke, hemorrhagic stroke, and venous thrombosis (VT). Patients and methods: We used data from two ongoing population‐based case–control studies of MI, stroke, and VT. Cases included hypertensive adults and postmenopausal women with incident non‐fatal MI (n = 1063), ischemic stroke (n = 469), and hemorrhagic stroke (n = 91), and postmenopausal women with incident non‐fatal VT (n = 504). Controls were frequency matched to cases on age, sex, hypertension status, and year of identification. ABO genotypes were determined using single‐nucleotide polymorphisms, and subjects were grouped by diplotype according to the presence of O¹, O², A¹¹, A² and B alleles. Logistic regression was used to test the association of diplotypes with risk of each outcome. Results: As compared with the O¹O¹ group, the A¹¹ allele was associated with an increased risk of VT [odds ratio (OR) 1.79; 95% confidence interval (CI) 1.41–2.26] and MI (OR 1.23; 95% CI  1.05–1.44). The B allele was associated with an increased risk of VT (OR 1.82; 95% CI  1.29–2.57) and ischemic stroke (OR 1.59; 95% CI  1.17–2.17). The AB diplotype category was associated with a 2.7‐fold risk of VT (OR 2.70; 95% CI  1.73–4.21). No other associations reached significance. Conclusions: The VT and MI findings are confirmatory, and the ischemic stroke finding with the B allele is a novel finding and needs replication.     

G-455A polymorphism of the fibrinogen beta gene and deep vein thrombosis

BACKGROUND: Elevated fibrinogen levels have been linked to increased risk for deep venous thrombosis, although it is not clear whether fibrinogen is causal or rather a marker for the presence of other risk factors. A common G/A polymorphism in the gene for the fibrinogen beta-chain (FGB G-455A) is associated with elevated fibrinogen levels. The present study was designed to analyze the role of this genetic marker for deep venous thrombosis. MATERIALS AND METHODS: We performed a case-control study including 307 patients with documented deep venous thrombosis and 316 control subjects. beta-fibrinogen genotypes were determined by allele-specific polymerase chain reaction. RESULTS: GG, GA and AA genotype frequencies were similar among the patients (53.1%, 41.0, 5.9) and controls (51.6%, 42.1, 6.3; P = 0.92). Fibrinogen levels of the patients (median 3.72 g l-1; range 1.93-11.6) did not differ significantly from those of the controls (3.76; 2.17-9.99). Carriers of the homozygous AA genotype had significantly higher fibrinogen levels than noncarriers (patients: 5.32 vs. 3.59; P = 0.024; controls: 6.29 vs. 3.72; P = 0.048). CONCLUSION: Our data suggest that the fibrinogen-elevating FGB G-455A gene polymorphism is not linked to an increased risk for deep venous thrombosis.     

Genetic variants and haplotypes of lipoprotein associated phospholipase A2 and their influence on cardiovascular disease (The Ludwigshafen Risk and Cardiovascular Health Study)

Summary.  Background:   There is increasing evidence that lipoprotein-associated phospholipase A2 (LpPLA2) is associated with cardiovascular disease. However, it is still unclear whether LpPLA2 is simply a marker or has a causal role as either a pro- or anti-atherogenic factor. Methods:   We analyzed the association of five polymorphisms (−1357G>A, −403T>C, Arg92His, Ile198Thr, Ala379Val) and related haplotypes at the PLA2G7 locus with angiographic coronary artery disease (CAD), plasma LpPLA2 activity, and long-term survival in 3234 patients scheduled for coronary angiography. Results:   The promoter variant −403C and His⁹² were associated with a decrease and Val³⁷⁹ with an increase in plasma LpPLA2 activity. Both coding variants revealed a clear gene-dose effect. Interestingly, the rare Thr¹⁹⁸ allele, which was not associated with any change in plasma LpPLA2 activity, was more frequent in subjects without CAD ( P  = 0.009), with an adjusted odds ratio for CAD of 0.69 (95% CI: 0.49–0.96; P  = 0.029). None of the analyzed variants showed any robust association with all-cause or cardiovascular mortality. Conclusion:   Irrespective of the significant association between some variants with plasma LpPLA2 activity, it is still unclear whether these polymorphisms or haplotypes are associated with the risk and outcome of cardiovascular disease in Caucasians.     

纤维蛋白原基因多态性与缺血性心脑血管病的关系

目的：调查健康人、心肌梗死患者及脑梗死患者的纤维蛋白原（Fg)β-455G/A、-148C/T、448G/A基因多态性频率分布、Fg分子反应性及与血浆Fg水平的关系。方法：用限制性片段长度多态性分析基因频率分布，用计算机辅助的纤维蛋白单体聚合反应分析方法和Clauss法分析血浆Fg水平。结果：等位基因－455A、－148T和448A在正常人中的频率分别是0．185，0．194及0．192；在心肌梗死患者中的频率分别是0．295，0．318及0．307；在脑梗死患者中的频率分别是0．177，0．193及0．182。心肌梗死患者中－455A、－148T和448A的频率比健康人明显升高。3个多态性位点－455G、－148C和448G或－455A、－148T和448A分别紧密连锁，符合率超过98％。心脑血管病患者的Fg功能明显增高且与Fg水平相关。3个多态性位点不同基因型组血浆Fg水平差异无显著性。结论：3对等位基因紧密连锁不平衡，不同基因型组血浆Fg水平差异无显著性，心肌梗死患者中－455A、－148T和448A的频率比健康人明显升高。提示Fgβ-455G/A、-148C/T和448G／A三种基因多态性与血浆Fg水平无关，而与心肌梗死的发病相关。心脑血管病患者不仅Fg功能明显增高，且与Fg水平相关。     

Lipoprotein(a) and ultrasonographically determined early atherosclerotic changes in the carotid and femoral artery

Summary.  Recent studies suggest that high lipoprotein(a) [Lp(a)] plasma levels are associated with symptomatic ischemic cardiovascular disease. We examined whether Lp(a) plasma levels are associated with early atherosclerotic vessel wall changes in a group of asymptomatic subjects. In a group of 142 asymptomatic men, the intima-media thickness (IMT) in the common carotid artery, the carotid bifurcation and the common femoral artery was determined by B-mode ultrasonography. In addition to Lp(a) levels, established risk factors, such as blood pressure and cholesterol levels were determined. Lipoprotein(a) values ranged from 2 mg L⁻¹ to 900 mg L⁻¹ (median 145 mg L⁻¹). Linear regression analysis showed a clear association of IMT with the established risk factors but not with Lp(a) [regression coefficient carotid artery −0.0003, 95% confidence interval (CI) −0.002–0.001; regression coefficient femoral artery −0.0003, 95% CI −0.004–0.003]. We found no increased intima-media thickness in the carotid or femoral artery at high levels of Lp(a). Lipoprotein(a) levels are not associated with early atherosclerotic vessel wall changes in the carotid or femoral artery.     

Peak thrombin generation and subsequent venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE) study

Summary.  Background : Thrombin is an enzyme that is essential for the acceleration of the coagulation cascade and the conversion of fibrinogen to clottable fibrin. Objectives : We evaluated the relationship of basal peak thrombin generation with the risk of future venous thromboembolism (VTE), and determined whether associations were independent of other coagulation markers. Methods : The Longitudinal Investigation of Thromboembolism Etiology (LITE) study investigated VTE in two prospective population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS). Peak thrombin generation was measured on stored plasma in a nested case–control sample (434 cases and 1004 controls). Logistic regression was used to estimate the relationship of peak thrombin generation with VTE, adjusted for age, sex, race, center, and body mass index. Mediation was evaluated by additionally adjusting for factor VIII and D-dimer. Results : Relative to the first quartile of peak thrombin generation, the odds ratio (OR) of VTE for those above the median was 1.74 [95% confidence interval (CI) 1.28–2.37]. The association was modestly attenuated by adjustment for FVIII and D-dimer (OR 1.47, 95% CI 1.05–2.05). Associations appeared to be stronger for idiopathic than for secondary VTE. Elevated peak thrombin generation more than added to the VTE risk associated with FV Leiden or low activated partial thromboplastin time. Conclusions : In this prospective study of two independent cohorts, elevated basal peak thrombin generation was associated with subsequent risk of VTE, independently of established VTE risk factors.     

Molecular mechanisms accounting for fibrinogen deficiency: from large deletions to intracellular retention of misfolded proteins

Summary.  Fibrinogen, the soluble precursor of fibrin, which is the main protein constituent of the blood clot, is synthesized in hepatocytes in the form of a hexamer composed of two sets of three polypeptides (Aα, Bβ, and γ). Each polypeptide is encoded by a distinct gene, FGA, FGB and FGG , all three clustered in a region of 50 kb on 4q32. Congenital afibrinogenemia is characterized by the complete absence of fibrinogen. The first causative mutation for this disease was identified in Geneva in a non-consanguineous Swiss family in 1999: the four patients were homozygous for a large deletion in the fibrinogen cluster, which eliminated almost the entire FGA genomic sequence. Mutations in the fibrinogen genes may lead to deficiency of fibrinogen by several mechanisms: acting at the DNA level, at the RNA level by affecting mRNA splicing or stability, or at the protein level by affecting protein synthesis, assembly or secretion. Recent reviews have provided helpful updates for the rapidly growing number of causative mutations identified in patients with fibrinogen deficiencies, either afibrinogenemia or hypofibrinogenemia. The aim of this review is to highlight specifically the subset of mutations that allow fibrinogen chain synthesis and hexamer assembly but impair secretion. Indeed, functional studies of these mutations have shed light on the specific sequences and structures in the fibrinogen molecule involved in the quality control of fibrinogen secretion.     

The β fibrinogen gene G-455-A polymorphism is a risk factor for Legg–Perthes disease

Summary  Legg–Perthes disease is a pediatric hip disorder characterized by avascular necrosis of the femoral head. The etiology of Legg–Perthes disease may involve repeated interruptions of the blood supply to the proximal femur. Thus, the role of thrombosis in Legg–Perthes disease is of interest. The focus of this analysis is an evaluation of the relationship between Legg–Perthes disease and the β fibrinogen gene G-455-A polymorphism in 55 cases of Legg–Perthes disease and 56 age, race, and gender-matched healthy controls. Parents of subjects completed a questionnaire about their child's lifestyle and medical history. Blood was obtained for plasma and DNA analysis. Study subjects were predominantly white (93%), male (77%) and under age 16 (70%). Cases were more likely to be exposed to passive smoke than were controls (odds ratio 5.6, 95% confidence interval 2.0–12.0). Assuming a dominant genetic model, individuals who possessed either the G/A or A/A genotype were over three times more likely to have Legg–Perthes disease compared to those without the polymorphism (odds ratio 3.4, 95% confidence interval 1.5–7.8). Separate analyzes by smoke exposure revealed that the excess risk of the G-455-A polymorphism occurred in those exposed (odds ratio 7.0) as opposed to those unexposed to passive smoke (odds ratio 1.9). Although this difference in the odds ratios is not statistically significant ( P  = 0.2), it suggests a possible interactive effect of cigarette smoke and the b fibrinogen gene G-455-A polymorphism in the risk of developing Legg–Perthes disease.     

Low protein C and incidence of ischemic stroke and coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study

Summary.  Background:  Protein C is an important plasma natural anticoagulant. Although protein C deficiency increases risk of venous thrombosis, it remains uncertain whether low protein C increases risk of atherothrombosis. Objective:  To examine whether low protein C may be a risk factor for ischemic stroke or coronary events in a prospective population-based study. Patients/Methods:  The Atherosclerosis Risk in Communities Study assessed protein C antigen by ELISA at baseline in 1987–89 and followed participants ( n  =   13 879) for incident ischemic stroke or coronary events through 2005. Results:  Over a median of 16.9 years of follow-up, 613 ischemic strokes and 1257 coronary heart disease events occurred. Protein C was inversely associated with incidence of ischemic stroke. Adjusted for multiple risk factors, the rate ratios (95% CIs) from highest to lowest quintiles were 1.0, 1.16 (0.90–1.50), 1.22 (0.94–1.58), 1.18 (0.90–1.55) and 1.52 (1.17–1.98). This inverse association was stronger for non-lacunar and cardioembolic stroke than for lacunar stroke. In contrast, there was a positive association between protein C and coronary heart disease in incompletely adjusted models, but no association after adjustment for plasma lipids. Conclusions:  In this cohort study, low protein C was a risk factor for incident ischemic stroke but not coronary heart disease. Levels of protein C associated with stroke risk were not restricted to the traditional 'deficient' range for protein C (< 0.5 percentile), suggesting that other etiologies for a lower protein C, or genetic variants associated with more subtle changes in protein C, are playing a role in disease pathogenesis.     

Prior use of antithrombotic agents and neurological functional outcome at discharge in patients with ischemic stroke

Summary.  Background:  Studies in experimental animals have suggested that antithrombotic agents may have a neuroprotective effect after an ischemic injury. The aim of this study was to analyze the effect of prior use of antithrombotic agents (antiplatelets or anticoagulants) on neurological functional outcome in patients with acute ischemic stroke. Subjects and methods:  Consecutive patients included in the Perugia Stroke Registry were considered for this analysis. Neurological functional outcome was evaluated at discharge using the modified Rankin Scale (mRS ≥ 3 disabling stroke). Results:  Of the 1921 patients included in the analysis (mean age 76.3 ± 12.5 years; 53% males), 662 (34.5%) were on antithrombotic treatment (581 antiplatelets, 71 anticoagulants and 10 antiplatelets associated with anticoagulants). One hundred and twenty-two patients (6.4%) died in hospital; at discharge 712 patients (37.1%) were disabled and 1087 patients (56.6%) were non-disabled. Fifty-four (44.3%) of the deceased patients and 270 (37.9%) of disabled patients were on antithrombotic treatment, while 338 (31.1%) non-disabled patients were taking antithrombotic agents. From multivariate analysis, age and stroke severity were associated with an adverse outcome. Male gender, dyslipidemia, stroke due to small vessel disease and no history of previous stroke were associated with an improved outcome, while no correlation was found between prior use of antithrombotic agents and outcome (mortality odds ratio; OR = 1.32, 95% confidence interval; CI 0.85–2.04; P  = 0.20, mortality or disability OR = 0.95, 95% CI 0.72–1.25; P  = 0.80). Conclusion:  Prior use of antithrombotic agents does not improve the functional outcome in patients with acute ischemic stroke.     

Fibrinogen is a marker for nephropathy and peripheral vascular disease in type 1 diabetes: studies of plasma fibrinogen and fibrinogen gene polymorphism in the DCCT/EDIC cohort

We examined whether plasma fibrinogen levels and the beta-fibrinogen gene G(-455)-->A polymorphism were related to microvascular or macrovascular disease in patients (n = 909) with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/ EDIC). Univariate regression showed that fibrinogen levels were correlated with BMI (r = 0.15; P < 0.0001), HbA(1c) (r = 0.11; P = 0.0014), total cholesterol (r = 0.17; P < 0.0001), and LDL cholesterol (r = 0.16; P < 0.0001) in all patients. In men, but not women, waist-to-hip ratio (r = 0.20; P < 0.0001) and triglycerides (r = 0.13; P = 0.0047) also became powerful predictors of fibrinogen level; in women, but not men, fibrinogen was correlated with both diastolic (r = 0.16; P = 0.0011) and systolic (r = 0.11; P = 0.0241) blood pressure. Fibrinogen was correlated with urinary albumin excretion rates in men (r = 0.13; P = 0.0033), but not in women. In both sexes, however, the development of proteinuria (albumin excretion >300 mg/24 h) was accompanied by 1.5-fold increment in plasma fibrinogen compared with patients with normal excretion or microalbuminuria. In addition, high fibrinogen levels were associated with a lower average ankle-brachial index in women (r = -0.13; P = 0.0075), but not men. Multiple regression analyses demonstrated that plasma fibrinogen was independently correlated with high albumin excretion rate in men, and with low average ankle-brachial index in women. Fibrinogen was not correlated with the severity of retinopathy. Carotid artery intima-medial thickness was not correlated with fibrinogen, and the G(-455)-->A polymorphism in the 5' promoter region of the beta-fibrinogen gene did not influence circulating fibrinogen levels. However, the presence of the more common G(-455) allele was associated with greater intima-medial thickness in the internal carotid artery (ANCOVA P = 0.045). Last, hyperfibrinogenemia in type 1 diabetes is associated with components of the insulin resistance syndrome trait cluster, and the association is influenced by sex.     

β-纤维蛋白原-455 G/A基因多态性与脑梗死的关系

目的:探讨β-纤维蛋白原-455 G/A(-βFg-455G/A)基因多态性与中国东北地区汉族脑梗死发病(CI)的关系。方法:应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法,检测脑梗死组(CI组)72例和对照组69例-βFg-455G/A基因的多态性,并测定其血浆纤维蛋白原(Fg)的含量。结果:经χ2检验,各基因型频率和等位基因频率在两组间均无显著性差异(P>0.05);CI组血浆Fg水平(2.70±1.05 g/L)和对照组(2.62±0.51 g/L)比较差异无显著性意义(P>0.05)。结论:本研究未发现-βFg-455G/A基因多态性与脑梗死之间存在相关关系。     

Soluble P-selectin levels, P-selectin polymorphisms and cardiovascular disease

Summary.  P-selectin is a member of the selectin family of cell adhesion molecules which are important in the transient attachment of leukocytes to endothelial cells and platelets. A number of polymorphisms in the gene encoding P-selectin have been identified. Objectives were to investigate the relationship of soluble P (sP)-selectin with P-selectin gene polymorphisms and coronary artery disease (CAD). Two hundred and forty-nine patients, with extent of CAD characterized by ≥50% stenosis in one or more coronary arteries, and 252 healthy controls were studied. Soluble P-selectin was significantly higher in the patients than controls after adjustment for age, sex and smoking [patients 49.8 (47.5–52.1) ng mL⁻¹; controls 46.7 (44.5–49.1) ng mL⁻¹, P  = 0.03). There was no association of sP-selectin with myocardial infarction (MI) or presence of ≥50% stenosis. The −1817 T/C, −1969 G/A and −2123 C/G (but not the Thr715Pro) polymorphisms were in strong linkage disequilibrium. The Thr715Pro polymorphism was significantly associated with sP-selectin even after adjustment for covariates [TT 48.9 (46.9–50.0) ng mL⁻¹; TP + PP 40.7 (38.1–43.6) ng mL⁻¹, P  < 0.0001]. A significant interaction of Thr715Pro and smoking status was identified in the determination of sP-selectin levels. There was no significant association of genotype at any of the polymorphism in relation to MI or stenosis. The Thr715Pro polymorphisms is associated with plasma sP-selectin. This association is modulated by smoking, although the underlying mechanism remains unclear.     

Factor V Leiden as a risk factor for preterm birth – a population‐based nested case–control study

Summary. Background: Preterm birth is a major cause of neonatal morbidity and mortality, occurring in 5–13% of deliveries in developed countries. Genetic thrombophilia can theoretically contribute to the induction of preterm delivery, but the role of thrombophilia as risk factor is unclear. Objectives: To assess factor V Leiden, FII G20210A and other selected inherited and acquired variables as risk factors for preterm birth. Patients/Methods: We performed a population‐based nested case–control study of 100 000 consecutive pregnancies in Finland. Cases and controls were identified by combining national registers. Clinical data were obtained from medical records and standardized questionnaires. We studied 324 cases with preterm delivery at or after 22 and before 37 completed weeks of gestation, and 752 controls. Results: FV Leiden was associated with a 2.4‐fold risk (95% confidence interval [CI] 1.3–4.6) of preterm birth in all pregnancies, and a 2.6‐fold risk (95% CI 1.4–5.1) in singleton pregnancies. FV Leiden was especially associated with late preterm birth at or after 32 weeks of pregnancy, with an odds ratio (OR) of 2.9 (95% CI 1.5–5.6) in all pregnancies and an OR of 3.1 (95% CI 1.6–6.2) in singleton pregnancies. FII G20210A was not associated with preterm birth. Twin pregnancy (OR 12.0, 95% CI 6.0–24.1) and a history of venous thrombosis (OR 3.8, 95% CI 1.4–9.8) were associated with increased risk. High educational level and modest overweight (body mass index 25–29.9 kg m^?2) had protective effects. Conclusions: Maternal carriage of FV Leiden was associated with increased risk of late but not early preterm birth. FII G20120A was not associated with preterm birth.     

Pharmacokinetics and pharmacodynamics of a new highly secured fibrinogen concentrate

Summary.  Background:  Inherited afibrinogenemia is a rare autosomal recessive disorder characterized by the absence or trace amounts of plasma fibrinogen inducing varying bleeding tendencies. Little is known about the pharmacokinetics of plasma-derived fibrinogen concentrates used in the treatment of afibrinogenemic patients. Objective: This open, prospective, multicenter study assessed the pharmacokinetic and pharmacodynamic profiles of FIBRINOGENE  T1 (FGT1; LFB, Les Ulis, France), a human fibrinogen concentrate treated with three specific biological safety steps. Patients/methods: Five adult patients with congenital afibrinogenemia received a single infusion of 0.06 g kg⁻¹ of FGT1 . Plasma samples drawn up to day 14 were assayed for fibrinogen antigen and activity and for coagulation parameters in a central laboratory. Results: Fibrinogen antigen and activity were similar and highly correlated, with very low between-patient variability for pharmacokinetic parameters. Fibrinogen levels increased rapidly and significantly, with a mean plasma concentration of 1.39 g L⁻¹ being achieved 1 h after the end of the infusion, leading to almost complete in vivo recovery (94%). The mean half-life was 3.4 days, with slow linear elimination, and the distribution was mainly restricted to the vascular compartment. Coagulation parameters were normalized after the infusion and during the following 6–10 days. FGT1 was well tolerated overall. Conclusions: FGT1 behaves like natural functional fibrinogen, and its pharmacokinetic properties are in line with those expected from a fibrinogen concentrate. Our findings suggest that FGT1 can restore efficient hemostasis in afibrinogenemic patients, and predict good clinical efficacy.