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The missing heritability of venous thrombosis: what about factor V Leiden heterogeneity?

Venous thrombosis (VT) is a complex pathology involving both environmental and genetic causes. Although its heritability is estimated to be ⁓ 50%, identifying the genetic background of the disease remains a major challenge. Some genetic variants that contribute to the risk have been identified in candidate genes, such as the factor V Leiden mutation. Other susceptibility single-nucleotide polymorphisms (SNPs) have been identified in unsuspected genes, such as SLC44A2 or TSPAN15, through high-throughput genotyping strategies, mostly in genomewide association studies (GWASs) [1]. However, even though those approaches have been successful in identifying new genes, much remains to be done to identify the missing heritability of VT, as known genetic variants explain only 5% of the heritability component. In addition, the incomplete penetrance of the identified VTrelated mutations/polymorphisms is still a challenge to overcome. The FV Leiden variant (F5) was identified years ago, and, despite being well known as a genetic risk factor for VT, is still not completely understood. Indeed, despite an allele frequency of ~ 5% in the general population of European descent, only 10% of F5 heterozygotes will develop VTs, with various degrees of severity, in their lifetimes. Scientists have attempted to explain the incomplete penetrance and the variable clinical picture of VT in F5 patients, leading to the identification of genetic interactions with other known thrombotic risk factors (antithrombin deficiency, protein C or protein S deficiency, and the prothrombin G20210A mutation). However, because < 2% of F5 heterozygotes are expected to carry one of these mutations, other genetic modifiers of the F5 phenotype are yet to be discovered. Identifying the genetic environment surrounding F5 that enhances or decreases its associated thrombotic phenotype appears to be an important challenge. Ginsburg’s group, in a recent and impressive mouse study, tried to identify genetic modifiers of the F5 phenotype [2]. Mice have a high degree of conservation of the R504/R506 activated protein C cleavage site within FV, and thus provide a good model for studying what happens in humans with F5.