ID: 204 Heritability of plasma D-dimer, clot turbidity and clot lysis in the Leeds Family Study

Abstract

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.