Objective-The relative balance between clot formation and fibrinolysis is considered to reflect thrombotic potential following vascular injury. The aims of the present study were to (1) to determine the contribution of genetic and environmental factors to variance in measures of clot structure/function in the Leeds Family Study, and (2) Key Words: heritability Ⅲ coagulation Ⅲ fibrinolysis Ⅲ metabolic syndrome Ⅲ cardiovascular disease T he development of cardiovascular disease (CVD) is associated with a major thrombotic component initiated by underlying vascular damage. In occlusive arterial disease the development of a platelet rich thrombus is supported by a fibrin mesh, with fibrin formation dependent on complex interactions between components of the coagulation cascade. A significant contribution of additive genetic factors in determining risk for thrombosis was indicated by the GAIT Study, in which genetic factors accounted for Ϸ60% of variation in risk. 1 All the genes encoding hemostatic factors are potential candidates for thrombosis and studies in families and twins have demonstrated significant contributions of additive genetic factors to variance in these intermediate phenotypes. [2][3][4][5][6][7][8][9] Significant genetic correlations between hemostatic factors and thrombosis were identified in the GAIT study, indicating shared genes regulate plasma levels of hemostatic factors and susceptibility to thrombosis. 1 Although genetic factors contribute to variance in hemostatic factors, associations between common genetic variants of the genes encoding a variety of hemostatic components and CVD have generally been inconsistent. 10 Clot formation and fibrinolysis are dynamic processes, and identification of genetic factors regulating individual hemostatic factors may be less informative in relation to cardiovascular risk than identifying genetic factors influencing more complex phenotypes reflecting fibrin structure/function. A study in twins indicated heritabilities of 0.39 and 0.46 for clot permeability and clot density, 11 suggesting that genetic factors are important determinants of these phenotypes.The limited studies which have evaluated fibrin clot structure/function in relation to CVD indicate that dense structures, with increased stiffness, decreased permeability, and decreased clot lysis are observed in subjects with CVD 12,13 and in relatives of individuals with CVD. 14 Further understanding of the genetic and environmental determinants of fibrin structure/function may help to identify novel factors which influence vascular risk, and, in the longer term, inform the development of novel therapeutics.The aims of the present study were to (1) to determine the contribution of genetic and environmental factors to variance in measures of clot structure/function in the Leeds Family Study and (2) to determine the relationship between measures of clot structure/function and the metabolic syndrome as an indicator of cardiovascular risk.

The aim of this study was to determine whether complement C3 is an indicator of coronary artery disease (CAD). We measured plasma C3 and CRP levels in 278 patients undergoing coronary angiography for typical symptoms of CAD and 269 healthy age and sex matched controls. C3 levels were significantly higher in patients compared with controls (1.15 g/l and 0.92 g/l respectively; p<0.001). In the patient group, C3 levels correlated with BMI, fasting glucose, HbA1c, fibrinogen, CRP and HDL in both men and women. CRP levels were also higher in patients compared with controls (1.14 mg/l and 0.86 mg/l respectively; p=0.005) and correlated with markers of the metabolic syndrome. In a logistic regression model including C3, smoking, hypertension, cholesterol and diabetes, C3 was independently associated with CAD with an odds ratio of 3.20 for a 1 SD increase in C3 levels. In contrast, CRP was not independently associated with CAD in a similar regression analysis. In conclusion, both C3 and CRP plasma levels are elevated in patients with symptoms of CAD. However, C3 seems to be a better indicator of CAD than CRP in this study, suggesting that C3 could be an additional marker for risk stratification in atherosclerosis.

Aim:The aim of this study was to evaluate the heritability of D-dimer, clot turbidity and clot lysis and to determine the contribution of haemostatic factors and candidate polymorphisms to variance of these measures in 504 subjects from 89 families in the Leeds Family Study. Methods: D-dimer was measured by ELISA (Biopool). Clot turbidity (lag time and maximum absorbance [max∆abs]) and time to 50% clot lysis (lysis time) were determined by analysing the time course of changes in absorbance of thrombin-induced clot formation and tPA-mediated clot dissolution in microtiter plates read at 340 nm. Results: The age and sex adjusted heritability of D-dimer was 0.07 (SE 0.09, p=0.13); age and sex accounted for 11.9% of variance, fibrinogen accounted for 6.5% and FXIII 1% of total variance. The age and sex adjusted heritability of lag time was 0.09 (SE 0.07, p=0.09); fibrinogen and FXIII together accounted for 3.3% of total variance. For max∆abs, the age and sex adjusted heritability was 0.22 (SE 0.08, p<0.001); age and sex accounted for 6.7% of variance, fibrinogen accounted for 32%, lag time 4% and tPA 0.5% of total variance. 16.8% of the heritability of max∆abs was unexplained by these variables. In bivariate analysis, there were significant genetic and environmental correlations between fibrinogen and max∆abs (rG=0.491, p=0.029; rE=0.677, p<0.001). The age and sex adjusted heritability of lysis time was 0.21 (SE 0.09, p=0.002); age and sex accounted for 5.4% of variance, and fibrinogen, FXIII, FVII, PAI-1 and lag time accounted for 6%, 2.3%, 3.2%, 9.9% and 5% of total variance, respectively. The FXIII Val34Leu polymorphism accounted for a further 1.3% and the beta fibrinogen -455 G/A polymorphism accounted for 0.5% of variance in lysis time. There was no residual heritability of lysis time after accounting for these variables. Bivariate analyses of clot lysis and haemostatic factors indicated that there was significant genetic correlation between lysis time and fibrinogen (rG=0.667, p=0.002; rE=0.140, p=0.14) and between lysis time and FVII (rG=0.655, p=0.003; rE=0.099, p=0.29). Significant genetic and environmental correlations were found between lysis time and PAI-1 (rG=0.491, p=0.037; rE=0.358, p<0.001). Conclusions: These data indicate that genetic factors contribute to variance in clot structure and function as assessed by max∆abs and clot lysis time, whereas the determinants of D-dimer and lag time are largely environmental. Common genetic factors contribute to covariance between max∆abs and fibrinogen and between lysis time and fibrinogen, PAI-1 and FVII.