In this issue of Blood, Desch et al1  use gene-based collapsing analysis to identify rare naturally occurring variants in genes that increase the risk for venous thromboembolism (VTE). Functional studies of variants in one of the genes identified shed light on how they contribute to VTE. Collectively, the reported findings improve our understanding of the genetic risk factors for VTE.

Deep vein thrombosis and pulmonary embolism (collectively VTE) represent life-threatening medical conditions with major burden for patients. The risk for VTE is influenced by several risk factors, such as surgery, prolonged hospitalization, older age, and lifestyle.2,3  Genetic factors play a major role in VTE risk as well. With all the genome-wide association studies performed to date, the most frequently occurring DNA variants in the population, for instance, the Factor V Leiden variant, have been identified.4  However, currently identified frequently occurring VTE DNA variants do not explain all the genetic predisposition. Independent DNA variants that occur very infrequently in the population are expected to be causal in many complex genetic disorders, including VTE, but most studies are not powered sufficiently to identify rare variants.5 

Desch et al undertook an elegant approach to identify these rare variants. They selected a cohort of ∼400 individuals with VTE without known risk factors to increase the chance of finding genetic factors. All VTE cases were evaluated with whole-exome sequencing. Next, they performed a gene-based collapsing analysis5  in which, on a per-gene basis, the total number of rare coding variants (with allele frequencies <0.05% in the general population) was compared with those in a large control cohort. In doing so, they identified different rare DNA coding variants in several genes in VTE vs control cases. The success of this approach was underscored by the fact that rare variants observed in 3 of the 4 most significant genes encode anticoagulant proteins, protein C and S, and antithrombin. Naturally, it is expected that the majority of the identified rare DNA variants impair anticoagulant function. This would result in impaired clot resolution and eventually VTE. Functional studies of these rare variants should demonstrate their impact on coagulation, and hence, qualify these as bona fide risk factors. Needless to say, the findings also underscore the importance of rare DNA variants in protein C, S, and antithrombin encoding genes in VTE risk.

A fourth gene, STAB2, was identified that exhibited >4 times more rare coding variants in VTE cases compared with controls. Thus, STAB2 has been identified as a new VTE gene. STAB2 encodes Stabilin-2, an endothelial cell surface scavenger receptor. Desch et al showed that all of the 7 studied rare VTE Stabilin-2 variants exhibited impaired intracellular transport, resulting in lower cell surface expression compared with control Stabilin-2. This is an important finding as Stabilin-2 can clear von Willebrand factor from circulation.6  von Willebrand factor plays a central role in clot formation, and high plasma levels of this factor may increase the risk of VTE. To substantiate their findings, Desch et al showed in a large independent control cohort that rare STAB2 variants are significantly associated with higher von Willebrand factor plasma levels, consistent with impaired clearance. Thus, rare STAB2 variants that impair intracellular Stabilin-2 transport and surface expression may explain the increased risk of VTE through impaired von Willebrand factor plasma clearance. Apart from the 4 aforementioned genes, several additional genes with lower significance were identified. For the vast majority of these genes, a role in clot formation and VTE remains to be uncovered.

How can we translate these findings into clinical practice? Before individual rare variants can be added in genetic VTE risk classification, functional tests demonstrating their role in clot formation and resolution need to be performed. For Stabilin-2 variants, the effect on von Willebrand factor clearance is important. Here, however, additional work is required as Stabilin-2 recognizes and clears plasma ligands like heparan and keratin sulfate and hyaluronic acid, in addition to von Willebrand factor. It is therefore conceivable that lower Stabilin-2 cell surface expression affects multiple processes and that certain variants may alter the recognition of one or more ligands instead of affecting surface expression.

In conclusion, the presented work provides in important improvements in our understanding of the genetic causes of the risk to develop VTE. Rare DNA variants are important. Smart approaches are required to perform bioinformatic and functional testing of these variants to determine their aggregate impact on the risk of VTE. In the future, their inclusion in genetic testing will improve our options to better predict the risk of VTE at the genetic level.

Conflict-of-interest disclosure: The author declares no competing financial interests.

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