Unraveling Protein S Deficiency: Insights from a Population-Based Multiomic Study

Protein S deficiency challenges venous thromboembolism (VTE) management. Guidelines discourage routine protein S testing in patients requiring lifelong anticoagulation or with unprovoked/recurrent VTE. Questions persist about the role of genetics in these patients. This large-scale (>600,000 individuals), population-based multiomic study from U.K and U.S. datasets clarifies the prevalence of PROS1 variants and their relationship to circulating protein S levels and thrombosis risk. The researchers used the functional impact score (FIS; range 0–1), which categorizes gene variants based on their evolutionary conservation; higher scores predict more-severe disruption of the protein's function.

The results were as follows:

• High-risk PROS1 variants (FIS=1, frameshift and splice site mutations) are rare (0.01% prevalence), associated with severe protein S deficiency (~50% of normal levels), and confer a 14-fold increased risk for VTE.
• Moderate-risk PROS1 variants (FIS >0.7, missense mutations) are more common (~0.2, have variable penetrance and impact on protein S levels, and confer lower risk of VTE (~2-fold).
• PROS1 variants are not associated with increased risk for myocardial infarction, peripheral arterial disease, or ischemic stroke.
• Protein S deficiency in individuals with wild-type PROS1 (no variants) is associated with a 2.5-fold risk for VTE and peripheral artery disease.