PROS1 genotype phenotype relationships in a large cohort of adults with suspicion of inherited quantitative protein S deficiency

Summary

Inherited protein S deficiency (PSD) is an established risk factor for venous thromboembolism (VTE). However, data are conflicting concerning risk of VTE associated with decreased free PS level (FPS) and information on PROS1 genotype-phenotype relationship is sparse. In a retrospective cohort of 579 patients with inherited type I/III deficiency suspicion, PROS1 genotyping was performed and the effect of genotype on FPS and on VTE risk was investigated. We found 116 (including 65 novel) detrimental mutations (DM) in 222 (type I/III in 194, type II in 28), PS Heerlen in 74, possibly non DM in 38 and no mutation in 245 subjects. Among DMs, type I/IIIDMs only were found in subjects with FPS<30 %. Prevalence of type I/III DM decreased with increasing FPS level. Risk of VT associated with FPS level and genotype was studied in the 467 subjects with personal or family history of thrombosis. Only type I/IIIDM carriers presented with an increased risk of VTE [1.41 (95%CI (1.05–1.89)] compared to subjects with no mutation. Among the group of type I/IIIDM heterozygotes and subjects with no mutation, the optimal FPS cut-off point for identifying subjects at increased VTE risk was searched for. We found that only subjects with FPS<30% and type I/IIIDM presented with an increased risk [1.48 (95%CI 1.08–2.04)]. Our findings confirm the value of a cut-off FPS level for identifying subjects at increased VTE risk far below the lower limit of the normal range and suggest a place for PROS1 genotyping in PSD diagnosis strategy.

Keywords

Coagulation inhibitor - protein S - PROS1 - thrombophilia - venous thrombosis

• References

• 1 Castoldi E, Hackeng TM. Regulation of coagulation by protein S. Curr Opin He-matol 2008; 15: 529-536.
• 2 Garcia de Frutos P, Fuentes-Prior P, Hurtado B. et al. Molecular basis of protein S deficiency. Thromb Haemost 2007; 98: 543-545.
• 3 Castoldi E, Maurissen LFA, Tormene D. et al. Similar hypercoagulable state and thrombosis risk in type I and type III protein S-deficient individuals from families with mixed type I/III protein S deficiency. Haematologica 2010; 95: 1563-1571.
• 4 Makris M, Leach M, Beauchamp NJ. et al. Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of PS. Blood 2000; 95: 1935-1941.
• 5 Brouwer JLP, Veeger NJGM, Van der Schaaf W. et al. Difference in absolute risk of venous and arterial thrombosis between familial protein S deficiency type I and type III. Results from a family cohort study to assess the clinical impact of a laboratory test-based classification. Brit J Haematol 2005; 128: 703-710.
• 6 Biguzzi E, Razzari C, Lane DA. et al. and protein S Italian team (PROSIT). Molecular diversity and thrombotic risk in protein S deficiency: the PROSIT study. Hum Mut 2005; 25: 259-269.
• 7 Lijfering WM, Mulder R, Ten Kate MK. et al. Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives. Blood 2009; 113: 1225-1230.
• 8 Mahmoodi BK, Brouwer JLP, Ten Cate MK. et al. A prospective cohort study on absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin. J Thromb Haemost 2010; 8: 1193-1200.
• 9 Simmonds RE, Ireland H, Lane DA. et al. Clarification on the risk of venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with characterized gene defect. Ann Intern Med 1998; 128: 8-14.
• 10 Koster T, Rosendaal FR, Briet E. et al. Protein C deficiency in a controlled series of unselected patients: an infrequent but clear risk factor for venous thrombosis (Leiden thrombophilia study). Blood 1995; 10: 2756-2761.
• 11 Faioni EM, Valsecchi C, Taioli E. et al. Free protein S deficiency is a risk factor for venous thrombosis. Thromb Haemost 1997; 78: 1343-1346.
• 12 Pintao MC, Ribeiro DD, Bezemer ID. et al. Protein S levels and the risk of venous thrombosis. Results from the MEGA case-control study. Blood 2013; 122: 3210-3219.
• 13 Liberti G, Bertina RM, Rosendaal FR. Hormonal state rather than age influences cut-off values of protein S: reevaluation of the thrombotic risk associated with protein S deficiency. Thromb Haemost 1999; 82: 1093-1096.
• 14 Bucciarelli P, Passamonti SM, Biguzzi E. et al. Low borderline plasma levels of antithrombin, protein C and protein S are risk factors for venous thromboem-bolism. J Thromb Haemost 2012; 10: 1783-1791.
• 15 Gandrille S, Borgel D, Eschwege-Gufflet V. et al. Identification of 15 different candidate causal point mutations and three polymorphisms in 19 patients with protein S deficiency using a scanning method for the analysis of the protein S active gene. Blood 1995; 85: 130-138.
• 16 Hall AJ, Peake IR, Winship PR. Regulation of the human protein S gene promoter by liver enriched transcription factors. Brit J Haematol 2006; 135: 538-546.
• 17 Ng PC, Henikoff S. SIFT: Predicting amino-acid changes that affect protein function. Nucleic Acids Res 2003; 30: 3812-3814.
• 18 Adzhubei IA, Schmidt S, Peshkin L. et al. A method and server for predicting damaging missense mutations. Nature Methods 2010; 7: 248-249.
• 19 Houdayer C. In silico prediction of splice-affecting nucleotide variants. In silico tools for gene discovery. Methods Mol Biol 2011; 760: 269-281.
• 20 Contal C, O’Quigley J. An application of change point methods in studying the effect of age on survival in breast cancer. Comput Statistics Data Anal 1999; 30: 253-270.
• 21 Bertina RM, Ploos Van Amstel HK, Van Wunjgaarden A. et al. Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism of residue 406. Blood 1990; 75: 538-548.
• 22 Rockwell NC, Thorner JW. The kindest cuts of all crystal structures of Kex2 and furin reveal secrets of precursor processing. Trends Biochem Sci 2004; 29: 80-87.
• 23 Alhenc Gelas M, Canonico M, Morange PE. et al. GEHT Genetic Thrombophi-lia Group. Protein S inherited qualitative deficiency: novel mutations and phe-notypic influence. J Thromb Haemost 2010; 8: 2718-2726.
• 24 Caspers M, Pavlova A, Driesen J. et al. Deficiencies of antithrombin, protein C and protein S - Practical experience in genetic analysis of a large patient cohort. Thromb Haemost 2012; 108: 247-257.
• 25 Duebgen S, Kauke T, Marschall C. et al. Genotype and laboratory and clinical phenotypes of protein S deficiency. Am J Clin Pathol 2012; 137: 178-184.
• 26 Suzuki A, Sanda N, Miyawaki Y. et al. Down-regulation of PROS1 gene expression by 17β-estradiol via estrogen receptor α (ERa)-Sp1 interaction recruiting receptor-interacting Protein 140 and the corepressor-HDAC3 complex. J Biol Chem 2010; 285: 13444-13453.
• 27 Rezende SM, Lane D, Zöller B. et al. Genetic and phenotypic variability between families with hereditary protein S. thromb Haemost 2002; 87: 258-265.
• 28 Denis CV, Roberts SJ, Hackeng TM. et al. In vivo clearance of human protein S in a mouse model. Influence of C4b-binding protein and the Heerlen polymorphism. Arterioscl Thromb Vasc Biol 2005; 25: 2209-2215.
• 29 Mahmoodi BK, Brouwer JLP, Veeger NJGM. et al. Hereditary deficiency of protein C or protein S confers increased risk of arterial thromboembolic events at a young age. Results from a large family study cohort. Circulation 2008; 118: 1659-1167.