Genetic susceptibility to thrombosis and its relationship to physiologicalrisk factors: The GAIT study

Although there are a number of well-characterized genetic defects that lead to increased risk of thrombosis, little information is available on the re lative importance of genetic factors in thrombosis risk in the general popu lation We performed a family-based study of the genetics of thrombosis in t he Spanish population to assess the heritability of thrombosis and to ident ify the joint actions of genes on thrombosis risk and related quantitative hemostasis phenotypes. We examined 338 individuals in 21 extended pedigrees . Twelve pedigrees were ascertained through a proband with idiopathic throm bosis, and the remaining pedigrees were randomly ascertained. The heritabil ity of thrombosis liability and the genetic correlations between thrombosis and each of the quantitative risk factors were estimated by means of a nov el variance component method that used a multivariate threshold model. More than 60% of the variation in susceptibility to common thrombosis is attrib utable to genetic factors. Several quantitative risk factors exhibited sign ificant genetic correlations with thrombosis, indicating that some of the g enes that influence quantitative variation in these physiological correlate s also influence the risk of thrombosis. Traits that exhibited significant genetic correlations with thrombosis included levels of several coagulation factors (factors VII, VIII, IX, XI, XII, and von Willebrand), tissue plasm inogen activator, homocysteine, and the activated protein C ratio. This is the first study that quantifies the genetic component of susceptibility to common thrombosis. The high heritability of thrombosis risk and the signifi cant genetic correlations between thrombosis and related risk factors sugge st that the exploitation of correlated quantitative phenotypes will aid the search for susceptibility genes.