Genetic Susceptibility to Thrombosis and Its Relationship to Physiological Risk Factors: The GAIT Study

Abstract

Although there are a number of well-characterized genetic defects that lead to increased risk of thrombosis, little information is available on the relative importance of genetic factors in thrombosis risk in the general population. We performed a family-based study of the genetics of thrombosis in the Spanish population to assess the heritability of thrombosis and to identify the joint actions of genes on thrombosis risk and related quantitative hemostasis phenotypes. We examined 398 individuals in 21 extended pedigrees. Twelve pedigrees were ascertained through a proband with idiopathic thrombosis, and the remaining pedigrees were randomly ascertained. The heritability of thrombosis liability and the genetic correlations between thrombosis and each of the quantitative risk factors were estimated by means of a novel variance component method that used a multivariate threshold model. More than 60% of the variation in susceptibility to common thrombosis is attributable to genetic factors. Several quantitative risk factors exhibited significant genetic correlations with thrombosis, indicating that some of the genes that influence quantitative variation in these physiological correlates 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 plasminogen 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 significant genetic correlations between thrombosis and related risk factors suggest that the exploitation of correlated quantitative phenotypes will aid the search for susceptibility genes.

Familial risks of unusual forms of venous thrombosis: a nationwide epidemiological study in Sweden

“…In agreement with Souto et al [34], VTE was defined as not only DVT and PE but also superficial venous thrombosis (SVT) and other forms of venous thrombosis. This definition of VTE is common in studies of familial thrombotic risk of defined genetic defects [35][36][37].…”

A Genome Search for Genetic Determinants That Influence Plasma Fibrinogen Levels

“…This result supports our previous observation that multiple QTLs of varying effects will be involved in determining variation in hemostasis-related phenotypes. 12,13 Although we do not have information about the functional role of these SNPs, on the basis of these results, the most likely possibility is that they are in linkage disequilibrium with another putative functional polymorphism of the TCF1 gene, which might affect transcription activity of the HNF1 ␣-molecule or its expression. The next step will be to catalog the complete array of DNA sequence variation within the TCF1 gene through DNA resequencing.…”

“…11 Recently, as part of the Genetic Analysis of Idiopathic Thrombophila (GAIT) Project, we quantified the genetic contribution to susceptibility of thrombosis and related phenotypes in the Spanish population. 12,13 Of the quantitative risk factors studied, fibrinogen levels had a heritability of 34%, 12 indicating that genetic factors have an important effect on the quantitative variation in this phenotype. It has been reported that a proportion of this variation can be explained by polymorphisms in the fibrinogen genes, 14,15 especially in the fibrinogen ␤-chain gene, which regulates the limiting step in fibrinogen synthesis.…”

Genotyping of <i>CYP2C9</i> and <i>VKORC1</i> polymorphisms predicts south Indian patients with deep vein thrombosis as fast metabolizers of warfarin/acenocoumarin

“…Although certain risk factors have been identified, DVT is mainly caused by acquired factors including age, hospitalization, pregnancy, hormone therapy, cancer and surgery, and genetic risk factors including mutations and SNPs present in the genes actively involved in drug transport and metabolism. A number of various family and twin studies have revealed that genetic factors account for more than 60% of the risk for developing DVT (26,27). Regardless of ideal traditional treatment strategies with anticoagulants, a post-thrombotic syndrome often develops in one in four patients within a year while DVT recurs in one-third of patients within five years (28,29).…”