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DOI: 10.1055/s-0037-1614333
Genetic Modulation of Plasma Protein S Levels by Two Frequent Dimorphisms in the PROS1 Gene
Publication History
Received
18 March 1999
Accepted after revision
06 May 1999
Publication Date:
09 December 2017 (online)
Summary
We studied two polymorphisms located close to or within the 3’-untranslated (3’-UT) region of the PROS1 gene [an A to G transition at nt 2148 (Pro 626) and an A to C substitution at nt 2698] in 110 healthy volunteers. The allele frequency of the nt 2148 G variant was 35%, and that of the nt 2698 A variant was 27%. We found a relationship between the two dimorphisms (both separately and together) and the plasma total protein S antigen (tPS) level. The impact of the neutral Pro 626 dimorphism was more significant than that of nt 2698 C/A (p = 0.0003 and p = 0.013, respectively). The lowest tPS values were observed in subjects with the Pro 626;nt 2698 GG;CC genotype, and the highest values in those with the AA;AA genotype. Both polymorphisms acted independently of sex and age. The mechanisms by which the two polymorphisms regulate tPS synthesis were not revealed by the studies of platelet mRNA. This study provides the first evidence of a genetic modulation of tPS levels, which, in addition to age and sex, contributes to the wide normal range of tPS in plasma. Determination of these two polymorphisms could be a valuable additional tool for studying PS.
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References
- 1 Walker FJ. Regulation of activated protein C by a new protein. J Biol Chem 1980; 255: 5521-4.
- 2 Walker FJ. Regulation of activated protein C by protein S, the role of phospholipid in factor V inactivation. J Biol Chem 1981; 256: 11128-31.
- 3 Walker FJ, Chavin SI, Fay PJ. Inactivation of factor VIII by activated protein C and protein S. Arch Biochem Biophys 1987; 252: 322-8.
- 4 Heeb MJ, Mesters RM, Tans G, Rosing J, Griffin JH. Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C. J Biol Chem 1993; 268: 2872-7.
- 5 Heeb MJ, Rosing J, Bakker HM, Fernandez JA, Tans G, Griffin JH. Protein S binds to and inhibits factor Xa. Proc Natl Acad Sci USA 1994; 91: 2728-32.
- 6 Hackeng TM, Van’t Veer C, Meijers JCM, Bouma BN. Human protein S inhibits prothrombinase complex activity on endothelial cells via a direct interaction of protein S with factor Va and Xa. Evidence for an activated protein C independent anticoagulant function of protein S in plasma. J Biol Chem 1994; 269: 21051-8.
- 7 Dahlbäck B, Stenflo J. Hight molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein. Proc Natl Acad Sci USA 1981; 78: 2512-6.
- 8 Dahlbäck B. Inhibition of Protein Ca cofactor function of human and bovine protein S by C4b-binding protein. J Biol Chem 1986; 261: 12022-7.
- 9 Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL. Organization of the human protein S genes. Biochemistry 1990; 29: 7845-52.
- 10 Ploos van Amstel HK, van der Zanden AL, Bakker E, Reitsma PH, Bertina RM. Two genes homologous with human protein S cDNA are located on chromosome 3. Thromb Haemost 1987; 58: 982-7.
- 11 Ploos van Amstel HK, Reitsma PH, van der Logt PE, Bertina RM. Intronexon organization of the active human protein S gene PSa and its pseudogene PSβ: duplication and silencing during primate evolution. Biochemistry 1990; 29: 7853-61.
- 12 Edenbrandt CM, Lundwall A, Wydro R, Stenflo J. Molecular analysis of the gene for vitamin K-dependent protein S and its pseudogene. Cloning and partial gene organization. Biochemistry 1990; 29: 7861-8.
- 13 Comp PC, Nixon RR, Cooper MR, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-8.
- 14 Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64: 1297-1300.
- 15 Comp PC, Doray D, Patton D, Esmon CT. An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 1986; 67: 504-8.
- 16 Bertina RM. Hereditary protein S deficiency. Haemostasis 1985; 15: 241-6.
- 17 Briet E, Broekmans AW, Engesser L. Hereditary protein S deficiency. In: Protein C and related proteins. Bertina RM. Churchill Livingstone Ed.; 1988: 203-12.
- 18 Gouault-Heilmann M, Leroy-Matheron C, Levent M. Inherited protein S deficiency: clinical manifestations and laboratory findings in 63 patients. Thromb Res 1994; 76: 269-79.
- 19 Mannucci PM, Tripodi A, Bertina RM. Protein S deficiency associated with “juvenile” arterial and venous thrombosis. Thromb Haemost 1986; 55: 440.
- 20 Kamiya T, Sugihara T, Ogata K, Suzuki K, Nishika J, Hashimoto S, Yamagata K. Inherited deficiency of protein S in a Japanese family with recurrent venous thrombosis; a study of three generations. Blood 1986; 67: 406-10.
- 21 Rosenberg RD, Bauer KA. Thrombosis in inherited deficiencies of anti-thrombin III, protein C and protein S. Hum Pathol 1987; 18: 253-62.
- 22 Allaart RC, Aronson DC, Ruys T, Rosendaal FR, van Bockel JH, Bertina RM, Briët E. Hereditary protein S deficiency in young adults with arterial occlusive disease. Thromb Haemost 1990; 64: 206-10.
- 23 Bertina RM. Prevalence of hereditary thrombophilia and the identification of the genetic risk factors. Fibrinolysis 1988; 2: 7-13.
- 24 Broekmans AW, Van der Linden IK, Jansen-Koeter Y, Bertina RM. Prevalence of protein C (PC) and protein S (PS) deficiency in patients with thromboembolic disease. Thromb Res 1986; (Suppl. 06) 135a.
- 25 Koster T, Rosendaal FR, Briët E, Vandermeer FJM, Colly LP, Trienekens PH, Poort SR, Reitsma PH, Vandenbroucke JP. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis. Blood 1995; 85: 2756-61.
- 26 Gladson CL, Scharrer I, Hach V, Beck KH, Griffin JH. The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis. Thromb Haemost 1988; 59: 18-22.
- 27 Spek CA, Koster T, Rosendaal FR, Bertina RM, Reitsma PH. Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk. Arterioscler Thromb Vasc Biol 1995; 15: 214-8.
- 28 Lunghi B, Lacoviello L, Gemmati D, Dilasio MG, Castoldi E, Pinotti M, Castaman G, Redaelli R, Mariani G, Marchetti G, Bernardi F. Detection of new polymorphic markers in the Factor V gene: association with factor V levels in plasma. Thromb Haemost 1996; 75: 45-8.
- 29 Di Castelnuevo A, D’Orazio A, Amore C, Falanga A, Kluft C, Donati MB, Lacoviello L. Genetic modulation of coagulation factor VII plasma levels: contribution of different polymorphisms and gender-related effects. Thromb Haemost 1998; 80: 592-7.
- 30 Kanaji T, Okamura T, Osaki K, Kuroiwa M, Shimoda K, Hamasaki N, Niho Y. A common genetic polymorphism (46 C to T substitution) in the 5’-untranslated region of the coagulation factor XII gene is associated with low translation efficiency and decrease in plasma factor XII level. Blood 1998; 91: 2010-4.
- 31 Kangsadalampai S, Board PG. The Val34Leu polymorphism in the A subunit of coagulation factor XIII contributes to the large normal range in activity and demonstrates that the activation peptide plays a role in catalytic activity. Blood 1998; 92: 2766-70.
- 32 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-03.
- 33 Diepstraten CM, Ploos van Amstel JK, Reitsma PH, Bertina RM. A CCA/CCG neutral polymorphism in the codon for Pro 626 in the human protein S alpha (PROS1). Nucl Acid Res 1991; 19: 5091.
- 34 Mustafa S, Pabinger I, Mannhalter C. Two new frequent dimorphisms in the protein S (PROS1) gene. Thromb Haemost 1996; 76: 393-6.
- 35 Bell G, Karam J, Rutter W. Polymorphic region adjacent to the 5’ end of the human insulin gene. Proc Natl Acad Sci USA 1981; 78: 5759-63.
- 36 Leroy-Matheron C, Goault-Heilmann M, Aiach M, Gandrille S. A mutation of the protein S gene leading to an EGF-lacking protein in a family with qualitative (type II) deficiency. Blood 1998; 91: 4608-15.
- 37 Zöller B, Garcia de Frutos P, Dahlbäck B. Evaluation of the relationship between protein S and C4b-binding protein isoforms in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease. Blood 1995; 85: 3524-31.
- 38 Boerger LM, Morris PC, Thurnau GR, Esmon CT, Comp PC. Oral contraceptives and gender affect protein S status. Blood 1987; 69: 692-4.
- 39 Gari M, Kalkon L, Urrutia T, Valvé C, Borrell M, Fontcuberta J. The influence of low protein S plasma levels in young women on the definition of normal range. Thromb Res 1995; 73: 149-52.
- 40 Simmonds RE, Zöller B, Ireland H, Thompson E, Garcia de Frutos P, Dahlbäck B, Lane DA. Genetic and phenotypic analysis of a large (122-members) protein S-deficient kindred provides an explanation for the familial coexistence of type I and type III plasma phenotypes. Blood 1997; 89: 4364-70.
- 41 Faioni EM, Valsecchi C, Palla A, Taioli E, Razzari C, Mannucci PM. Free protein S deficiency is a risk factor for venous thrombosis. Thromb Haemost 1997; 78: 1343-6.