Genetic Modifiers of Venous Thrombosis
MetadataShow full item record
Venous thrombosis (VT) is defined as the formation of a blood clot within a vein. VT occurs in approximately 1 in 1000 people per year. Many genetic and environmental risk factors have been linked to the development of VT. Because of this, it is helpful to consider a “pro-blood clotting threshold”, which must be reached in order for a pathologic clot to occur. This threshold relies on a delicate balance between factors favoring clot formation and factors promoting clot dissolution (fibrinolysis) (figure 1). A mutation in the factor V gene, Factor V Leiden, is the most common known inherited risk factor for VT. However, penetrance is incomplete, only ~10% of FVL carriers experience significant blood clotting. It would be of great benefit to find additional genetic modifiers of FVL as well as thrombosis in general. This would allow for a more accurate risk assessment and potentially lead to new therapies for thrombosis patients. In order to identify modifying genes to VT, we will perform a ‘forward’ genetic screen in mice, for genes capable of suppression of a synthetic genotype that is normally lethal due to blood clotting. Any gene responsible for the suppression will be considered a candidate modifier gene to VT, and presumably a factor of the coagulation cascade. We previously generated a lethal interaction between FVL and another key coagulation factor, tissue factor pathway inhibitor (TFPI) in mice. When TFPI heterozygosity (Tfpi+/-) is combined with homozygosity for FVL (FvQ/Q), the result is neonatal lethality due to blood clotting. We have exploited this FVL/TFPI interaction as a phenotyping tool for a whole genome ENU mutagenesis screen in mice, in an attempt to identify ENU-induced thrombotic modifiers. Once suppressing genes are induced, positional cloning techniques will be done to locate and identify the genes responsible.