Background: Inherited protein S deficiency is a thrombophilic risk factor associated with venous thromboembolism. However, there is not much data on the impact of mutation position on thrombotic risk.
Objectives: The aim of this study was to evaluate the risk of thrombosis due to mutations located in the sex hormone-binding globulin (SHBG)-like region as opposed to the rest of the protein.
Methods: Genetic analysis of PROS1 was performed in 76 patients with suspected inherited protein S deficiency, and the effect of missense mutations present in the SHBG region on thrombosis risk was analyzed by statistical methods.
Results: We found 30 unique mutations (13 of them novel), of which 17 were missense mutations, in 70 patients. Patients with missense mutations were then divided into 2 groups: the "SHBG-region" mutation group (27 patients) and the "non-SHBG" group (24 patients). The multivariable binary logistic regression analysis showed that mutation position in the SHBG region of protein S is an independent risk factor for thrombosis in deficient patients (OR, 5.17; 95% CI, 1.29-20.65; P = .02). The patients with a mutation in the SHBG-like region also developed a thrombotic event at a younger age compared to the "non-SHBG" group in the Kaplan-Meier analysis (median thrombosis-free survival of 33 vs 47 years, respectively; P = .018).
Conclusion: Our findings show that a missense mutation located in the SHBG-like region may contribute to higher thrombotic risk rather than a missense mutation located elsewhere in the protein. However, as our cohort was relatively small, these findings should be taken with this limitation.
Keywords: missense mutation; protein S; protein S deficiency; thrombosis; venous thromboembolism.
© 2023 The Author(s).