Prevalence of the Prothrombin Gene Variant (nt20210A) in Venous Thrombosis and Arterial Disease

Summary

The prothrombin gene variant resulting form a G→A transition at position 20210 has been described as a common genetic risk factor for venous thrombosis. However, the risk for developing arterial disease is unknown. In this investigation, we studied 116 patients with venous thrombosis and 71 with arterial disease, all of whom were compared with 295 controls. Additionally, we also investigated the distribution of the prothrombin alleles among African descendents and Amazonian Indians from Brazil. The prevalence of 0.7% for 20210A allele in the control group increased to 4.3% (P = 0.021) among patients with venous thrombosis. There was also a high prevalence of the mutated allele in a selected arterial disease group (5.7%) without hyperlipoproteinemia, hypertension, and diabetes mellitus when compared to the controls (P = 0.013). Heterozygotes for the allele 20210A were common among individuals of African descent (2%) and rare among Indians. These data support the hypothesis that the prothrombin variant is a risk factor for venous thrombosis and suggest that it may also be a risk factor for arterial disease.

• References

• 1 Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 1991; 30: 10363-10370
• 2 Esmon CT. The protein C anticoagulant pathway. Arterioscler Thromb Vase Biol 1992; 12: 135-145
• 3 Gruber A, Harker LA, Hanson SR, Kelly AB, Griffin JH. Antithrombin effects of combining activated protein C and urokinase in nonhuman primates. Circulation 1991; 84: 2454-2462
• 4 Reitsma PH, Bemardi F, Doig RG, Grandille S, Greengard JS, Ireland H, Krawczak M, Lind B, Long GL, Poort SR, Saito H, Sala N, Witt I, Cooper D. Protein C deficiency: A database of mutations 1995 update. Thromb Haemost 1995; 73: 876-889
• 5 Lane DA, Olds RJ, Boisclair M, Chowdhury V, Thein SL, Cooper DN, Blajchman M, Perry D, Emmerich J, Aiach M. Antithrombin III mutation database: first update. Thromb Haemost 1993; 70: 361-369
• 6 Gomez E, Poort SR, Bertina RM, Reitsma PH. Identification of eight point mutation in protein S deficiency type I – Analysis of 15 pedigrees. Thromb Haemost 1995; 73: 750-755
• 7 Gandrille S, Borgel D, Eschwege Gufflet V, Aillaud M, Dreyfus M, Matheron C, Gaussem P, Abgrall JF, Jude B, Sié P, Toulon P, Aiach M. Identification of 15 different candidate causal point mutations and three polymorphism 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
• 8 Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-1008
• 9 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, Ronde H, van der VeldenPA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67
• 10 Simioni P, Zanardi S, Saracino A, Girolami A. Occurrence of arterial thrombosis in a cohort of patients with hereditary deficiency of clotting inhibitors. J Med 1992; 23: 61-74
• 11 Boers GHJ, Smals AGH, Trijbels FJM, Fowler B, Bakkeren JAJM, Schoonderwaldt HC, Kleijer WJ, Kloppenborg PWC. Heterozygosity for homocystinuria in peripheral and cerebral occlusive arterial disease. N Engl JMed 1985; 313: 709-15
• 12 Kang SS, Wong PWK, ZhouJ Sora J, Lessick M, Ruggie N. Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease. Metabolism 1988; 37: 611-613
• 13 Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324: 1149-1155
• 14 Falcon CR, Cattaneo M, Panzeri D, Martinelli L, Mannucci PM. High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis. Arterioscler Thromb Vase Biol 1994; 14: 1080-1083
• 15 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: 759-762
• 16 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variant 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: 3698-3703
• 17 Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677->Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. Thromb Haemost 1997; 77: 818-821
• 18 Lupus Anticoagulant Working Party.-Guidelines on testing for the lupus anticoagulant. J Clin Pathol 1991; 44: 885-889
• 19 Arruda VR, Annichino-Bizzacchi JM, Costa FF, Reitsma PH. Factor V Leiden (FVQ506) is common in Brazilian population. Am J Hematol 1995; 39: 242-243
• 20 Abildgaard U, Lie M, Oldergaard OR. Antithrombin (heparin cofactor) assay with new chromogenic substrates. Thromb Res 1977; 11: 549-553
• 21 Comp PC, Doray D, Patton D, Esmon CT. An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 1986; 67: 504-508
• 22 Odegaard OR, Try K, Abilgaard U. Protein C: a simplified semi-automated activity assay. Thromb Res 1986; 42: 257-262
• 23 Stein EA. Lipids, lipoproteins, and apolipoprotrein. In Fundamentals of Clinical Chemistry. Tieftz NW. ed. Philadelphia: W. B. Saunders; 1987. pp 449-481
• 24 Cavalli-Sforza LL, Piazza A, Menozzi P, Montain J. Reconstruction of human evolution: bringing together genetic archaelogical and linguistic data. Proc Natl Acad Sci USA 1988; 85: 6002-6006
• 25 Black FL, Salzano FM, Layrisse Z, Franco MHLP, Harris NS, Weimer TA. Restriction and persistence of polymorphisms of HLA and other blood genetic traits in the Parakanã Indians of Brazil. Am J Phys Anthr 1980; 52: 119-132
• 26 Millar SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from nucleated cell. Nucleic Acids Res 1988; 16: 1215
• 27 Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988; 239: 487-491
• 28 Dean AG, Dean JA, Coulombier D, Brendel KA, Smith DC, Burton AH, Dicker RC, Sullivan KM, Fagan RF, Amer TG. Epi Info version 6: a word processing database, and statistics program for epidemiology on microcomputers Atlanta. Center for Disease Control and Prevention. 1994
• 29 Ross R. Pathogenesis of atherosclerosis. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Colman RW, Hirsh J, Marder VJ, Salzman EW. eds. Philadelphia: J. B. Lippincott Company; 1994. pp 861-869
• 30 Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raughunathan TE, Vos HL. A common prothrombin variant (210210 G(A) increases the risk of myocardial infarction in young women. Thromb Haemost 1997; 78: 769 (Abstr)
• 31 Franco RF, Trip MD, ten Cate H, Prins MH, Kastelein JJP, Reitsma PH. The prevalence of the 20210 G→A mutation in the 3’-mistranslated region of the prothrombin gene in patients with premature coronary artery disease. Thromb Haemost 1997; 78: 769 (Abstr)
• 32 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-1134
• 33 Arruda VR, von Zuben PM, Soares MCP, Menezes R, Annichino-Bizzacchi JM, Costa FF. Very low incidence of Arg506→Gln mutation in the factor V gene among the Amazonian Indians and the Brazilian black population. Thromb Haemost 1996; 75: 860-861
• 34 Zivelin A, Griffin JH, Xu X, Pabinger I, Samama M, Conard J, Brenner B, Eldor A, Seligsohn U. A single genetic origin for a common caucasian risk factor for venous thrombosis. Blood 1997; 89: 397-402