Update to Soria et al.'s "F7 Gene and Clotting Factor VII Levels" (2005): Genetic Determinants of Quantitative Traits in Thrombotic Disease

The last 10 years have produced revolutionary advances in the field of human genetics, allowing a transition from the classical analysis of monogenic disorders to a new emphasis on the genetic basis of common disorders, such as thromboembolic disease. Thromboembolic disease is one of the most important causes of morbidity and mortality in industrialized nations and of great public health importance because of its high social and economic cost. Thus identification and characterization of specific loci and genes and the associated phenotypes involved in thrombotic risk will contribute to a greater understanding of the pathogenesis of this disease and will ultimately lead to the development of better diagnostic, prevention, and treatment strategies.

Genetic Base of Thrombosis Disease

Thrombosis is a complex disease that results from the interaction of genetic and environmental factors. The additive effect of genes is responsible for 61% of the variability in the susceptibility to thrombotic disease (Souto et al. 2000b), documenting the importance of genetic factors that influence this condition. Thus, in this genomic era, the search for genes involved in complex diseases, such as thrombophilia, is gaining momentum, as is the debate over gene-finding strategies (Rosendaal 2003; Souto 2003).

To date, the vast majority of analyses of genetic factors in thrombotic risk have been based on population case-control studies to test for association between genetic variants in specific genes and risk of disease. Although such studies provide important indirect evidence of genetic effects, they have a number of statistical weaknesses. These problems illustrate how difficult it is to genetically dissect complex diseases, such as thrombosis, mainly because of the heterogeneity of the disease outcomes, in which multiple physiologic and metabolic pathways are involved. A good way to better analyze these complex diseases is to look at measurable quantitative variation in phenotypes closely related to disease risk, known as intermediate phenotypes. These intermediate phenotypes have more power to localize and identify disease-related susceptibility genes than the examination of the highly complex disease outcome itself (Blangero et al. 2000). In this context, although the hunt for genes that influence thrombotic risk is still in its infancy, there are several examples of progress (Table 1).

Table 1.

Results from the GAIT Genome Scan for Thrombosis-Related Phenotypes

Quantitative Risk Factors for Thrombosis and Intermediate Phenotypes

The physiological cascade that underlies the normal formation of thrombin and the pathological endpoint of thrombosis is complex; many components involved in the coagulation and fibrinolytic pathways are known. The risk of thrombosis is influenced not only by abnormalities in these systems but also by quantitative variation within what is considered the normal physiological range of these parameters. In addition, it is likely that pathways and proteins outside the coagulation system are also involved in the pathogenesis of venous thrombosis. Loci harboring genes that contribute to the patterns of variation in such phenotypes have been named quantitative trait loci (QTLs). Intermediate risk factors can be used jointly with disease status to search the genome for QTLs that pleiotropically affect both risk factor and disease (Blangero et al. 2003; Soria et al. 2000, 2002).

In this context, we designed the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project, the main objective of which is to identify the genetic factors that determine the variation of quantitative phenotypes and their relationship with venous thrombosis. From this study, based on extended pedigrees, we demonstrated significant genetic correlations between thrombosis and activated protein C resistance, homocysteine, tissue plasminogen activator, von Willebrand factor, and clotting factors VII, VIII, IX, XI, and XII, suggesting pleiotropic influences on these quantitative measures and risk of thrombosis (Souto et al. 2000a). On the other hand, case-control association studies, such as the Leiden Thrombophilia Study (LETS), have been useful for identifying several complex phenotypes that increase the risk of venous...