Genetic Variants in the Protein S (PROS1) Gene and Protein S Deficiency in a Danish Population

Abstract

Protein S (PS) deficiency is a risk factor for venous thromboembolism (VTE) and can be caused by variants of the gene encoding PS (PROS1). This study aimed to evaluate the clinical value of molecular analysis of the PROS1 gene in PS-deficient participants. We performed Sanger sequencing of the coding region of the PROS1 gene and multiplex ligation-dependent probe amplification to exclude large structural rearrangements. Free PS was measured by a particle-enhanced immunoassay, while PS activity was assessed by a clotting method.

A total of 87 PS-deficient participants and family members were included. In 22 index participants, we identified 13 PROS1 coding variants. Five variants were novel. In 21 index participants, no coding sequence variants or structural rearrangements were identified. The free PS level was lower in index participants carrying a PROS1 variant compared with index participants with no variant (0.51 [0.32–0.61] vs. 0.62 [0.57–0.73] × 10³ IU/L; p < 0.05). The p.(Thr78Met) variant was associated with only slightly decreased free PS levels (0.59 [0.53–0.66] × 10³ IU/L) compared with the p.(Glu390Lys) variant (0.27 [0.24–0.37] × 10³ IU/L, p < 0.01). The frequency of VTE in participants with a coding PROS1 variant was 43 and 17% in the group with normal PROS1 gene (p = 0.05).

In conclusion, we report 13 PROS1 coding variants including five novel variants. PS levels differ by PROS1 variant and the frequency of VTE was higher when a coding PROS1 variant was present. Hence, molecular analysis of the PROS1 gene may add clinical value in the diagnostic work-up of PS deficiency.

Keywords

protein S deficiency - PROS1 - venous thromboembolism - inherited thrombophilia

Ethics

All participants gave written informed consent. The study was approved by the Central Denmark Region Committees on Biomedical Research Ethics (#1–10–72–333–14) and the Danish Data Protection Agency (#1–16–02–525–14). The study was conducted according to the Helsinki Declaration.

Publikationsverlauf

Eingereicht: 23. April 2021

Angenommen: 08. September 2021

Artikel online veröffentlicht:
28. Oktober 2021

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