The Prothrombin 20210A Allele Is the Most Prevalent Genetic Risk Factor for Venous Thromboembolism in the Spanish Population

Juan Carlos Souto; Inma Coll; Dolors Llobet; Elisabeth del Río; Arturo Oliver; José Mateo; Montserrat Borrell; Jordi Fontcuberta

doi:10.1055/s-0037-1615212

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1998; 80(03): 366-369
DOI: 10.1055/s-0037-1615212

Rapid Communications

Schattauer GmbH

The Prothrombin 20210A Allele Is the Most Prevalent Genetic Risk Factor for Venous Thromboembolism in the Spanish Population

Juan Carlos Souto

¹From Unitat d‘Hemostàsia i Trombosi

,

Inma Coll

¹From Unitat d‘Hemostàsia i Trombosi

,

Dolors Llobet

¹From Unitat d‘Hemostàsia i Trombosi

,

Elisabeth del Río

²From Servei de Genètica, Hospital de la Santa Creu i Sant Pau

,

Arturo Oliver

³From Fundació Puigvert, Barcelona, Spain

,

José Mateo

¹From Unitat d‘Hemostàsia i Trombosi

,

Montserrat Borrell

¹From Unitat d‘Hemostàsia i Trombosi

,

Jordi Fontcuberta

¹From Unitat d‘Hemostàsia i Trombosi

› Institutsangaben

Abstract

Summary

We investigated the prevalence of the new recently reported mutation in the prothrombin gene (20210 A) in a sample of 116 unrelated patients with venous thromboembolism. We found 20 heterozygous carriers (17.2%, CI 95% 10.4-21.1). In comparison, we observed 13 carriers among 201 healthy unmatched controls (6.5%, CI 3.5-10.8). The 20210 A mutation seems to increase the risk of venous thrombosis 3-fold (odds ratio 3.1, 95% CI 1.4-6.6). Considering only patients with a first event (n = 62) the OR was 2.0 (p = 0.18, NS) while those with recurrent events (n = 54) showed an OR of 5.9 (95% CI 2.5-14.4). A majority of heterozygous patients (55%) presented a second thrombophilic factor and 60% of affected females had their first event before 30 years of age, while on oral contraceptive treatment. The prevalence found in this study for healthy people is the highest reported to date. The 20210 A variant appears to be the most prevalent genetic risk factor among patients with thrombosis in our geographical area.

Volltext

Referenzen

References
1 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia: Part 1. Thromb Haemost 1996; 76: 651-62.
2 Koster T, Rosendaal FR, Briët E, van der Meer 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 (Leiden thrombophilia study). Blood 1995; 85: 2756-61.
3 Rosendaal FR. Risk factors for venous thrombosis: prevalence, risk, and interaction. Semin Hematol 1997; 34: 171-87.
4 Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen. Thromb Haemost 1995; 73: 151-61.
5 Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to a poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-6.
6 Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
7 Den Heijer M, Koster T, Blom HJ, Bos GMJ, Briët E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759-62.
8 Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Laboratory evaluation and clinical characteristics of 2132 consecutive unselected patients with venous thromboembolism - results of the Spanish multicentric study on thrombophilia. Thromb Haemost 1997; 77: 444-51.
9 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: 3698-703.
10 Cumming AM, Keeney S, Bhavnani M, Shwe KH, Hay CRM. The prothrombin gene variant: prevalence in a U.K. anticoagulant clinic population. Br J Haematol 1997; 98: 353-5.
11 Hillarp A, Zöller B, Svensson PJ, Dahlbäck B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 1997; 78: 990-2.
12 Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3’-untranslated region of the prothrombin gene. Br J Haematol 1997; 98: 907-9.
13 Corral J, González-Conejero R, Lozano ML, Rivera J, Heras I, Vicente V. The venous thrombosis risk factor 20210 A allele of the prothrombin gene is not a major risk factor for arterial thrombotic risk. Br J Haematol 1997; 99: 304-7.
14 Arruda VR, Annichino-Bizzacchi JM, Gonçalves MS, Costa FF. Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease. Thromb Haemost 1997; 78: 430-3.
15 Ferraresi P, Legnani C, Quaglio S, Castoldi E, Marchetti G, Palareti G, Bernardi F. Study of a G/A variation in the 3’ untranslated region of prothrombin mRNA in Italian patients with venous thrombosis. Thromb Haemost 1997 78 OC-1547 (abstract).
16 Howard TE, Marusa M, Boisza J, Young A, Sequeira J, Channell C, Guy C, Benson E, Duncan A. The prothrombin gene 3’-untranslated region mutation is frequently associated with factor V Leiden in thrombophilic patients and shows ethnic-specific variation in allele frequency. Blood 1998; 91: 1092-3 (letter).
17 Ólafsson I, Hjaltadóttir S, Önundarson PT, Pórarinsdóttir R, Haraldsdóttir V. Prevalence of factor V_Q506 and prothrombin 20210 A mutations in an apparently healthy Icelandic population and patients suffering from venous thrombosis. Thromb Haemost 1998; 79: 685-6 (letter).
18 De Maat MPM, Bladbjerg EM, Johansen LG, Gram J, Jespersen J. Absence of prothrombin mutation in Inuit (Greenland Eskimos). Thromb Haemost 1998; 79: 882.
19 Makris M, Preston FE, Beauchamp NJ, Cooper PC, Daly ME, Hampton KK, Bayliss P, Peake IR, Miller GJ. Coinheritance of the 20210ª allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemost 1997; 78: 1426-9.
20 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-46.
21 Hyland K, Bottiglieri T. Measurement of total plasma and cerebrospinal homocysteine by fluorescence following high-performance liquid chromatography and precolumn with ophthaldialdehyde. J Chromatography 1992; 79: 55-62.
22 Exner T, Rickard KA, Kronenberg H. A sensitive test demonstrating lupus anticoagulant and its behavioural patterns. Br J Haematol 1987; 40: 143-51.
23 Gharavi AE, Harris EN, Asherson RA, Hughes GRV. Anticardiolipin antibodies: isotype distribution and phospholipid specificity. Ann Rheum Dis 1987; 46: 1-6.
24 Miller SA, Dyckes AA, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res 1988; 16: 1215.
25 Koeleman BPC, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C deficient families. Blood 1994; 84: 1031-5.
26 Rosendaal FR, Doggen CJM, Zivelin A, Arruda VR, Aiach A, Siscovick DS, Hillarp A, Watzke HH, Bernardi F, Cumming AM, Preston FE, Reitsma PH. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79: 706-8.
27 Alhenc-Gelas M, Le Camp-Duchez V, Emmerich J, Frebourg T, Fiessinger JN, Borg JY, Aiach M. The A20210 allele of the prothrombin gene is not frequently associated with the factor V Arg 506 to Gln mutation in thrombophilic families. Blood 1997; 90: 1711.
28 Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453-7.