Prevalence of thrombophilic mutations of FV Leiden, prothrombin G20210A and PAI-1 4G/5G and their combinations in a group of 1,450 healthy middle-aged individuals in the Prague and Central Bohemian regions (results of FRET real-time PCR assay)

Czech version

Authors: Jan Kvasnička ¹; Jaroslava Hájková ¹; Petra Bobčíková ¹; Tomáš Kvasnička ¹; Daniela Dušková ²; Šárka Poletínová ²; Veronika Kieferová ²
Authors‘ workplace: Univerzita Karlova v Praze, Ústav klinické biochemie a laboratorní diagnostiky, Trombotické centrum a Centrální hematologické laboratoře ¹; Univerzita Karlova v Praze, 1. lékařská fakulta, Fakultní transfúzní oddělení VFN ²
Published in: Čas. Lék. čes. 2012; 151: 76-82
Category: Original Article

Overview

Background.
Factor V Leiden (G1691A) and prothrombin gene (FII G20210A) mutations are independent risk factors of venous thrombosis and this risk is further increased by the combined genotype 4G/4G PAI-1.

Aim.
The primary objective was to identify the frequency of mutations of minor alleles and genotypes of FVL, FII G20210A and PAI-1 4G/5G in healthy Caucasians in the Prague and Central Bohemia regions. The secondary objective was to identify the occurrence of their mutual combinations.

Method.
Genotyping was performed in 1,450 healthy individuals (blood donors, 981 men and 469 women) using robotic DNA isolation and subsequent PCR and melting curve analysis (Light Cycler 480 System, Roche).

Results.
The minor allele frequencies in FV Leiden and FII G20210A mutations were 4.5 % and 1.3% respectively. The frequency of the 4G PAI-1 allele was 55.9%. The genotype frequencies were as follows: GG 91.10%, GA 8.83% and AA 0.07% for FV Leiden; GG 97.38%, GA 2.55% and AA 0.07% for FII G20210A and 4G/4G 30.69%, 4G/5G 50.34% and 5G/5G 18.97% for PAI-1. No differences in these frequencies were found between the genders. The occurrence of the combined heterozygous FII and heterozygous FV Leiden mutations was 0.14%. The PAI-1 4G/4G genotype was combined with the heterozygous FV Leiden mutation in 2.83% of cases and with the heterozygous FII mutation in 0.62% of cases.

Conclusions.
The found frequencies of genotypes and alleles confirm a relatively high prevalence of hereditary thrombophilia in the Czech Republic.

Key words:
FV Leiden, FII G20210A, PAI-1 4G/5G, genotype, alleles, prevalence.

Sources

1. Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality.Thromb Haemost 2007; 98: 756–764.

2. Oger E et EPI-GETBO Study Group. Incidence of venous thromboembolism: A community-based study in Western France. Thromb Haemost 2000; 83: 657–660.

3. White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107(Suppl 1): 4–8.

4. Silverstein MD, Heit J, Mohr DN, Petterson T M, O’Fallon M, Melton J. Trends in the incidence of deep velus thrombosis and pulmonary embolism: a 25-year population-based, cohort study. Arch Intern Med 1998;158: 585–593.

5. Puchmayer V, Roztočil K. Praktická angiologie. Praha: Triton 2000; s. 191.

6. Chochola M, Vařejka P, Staněk F, et al. Novinky v diagnostice a léčbě hluboké žilní trombózy dolních končetin. Čas Lék čes 2000; 139: 583.

7. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167–1173.

8. Margaglione M, Grandone E. Population genetics of venous thromboembolism. A narrative review. Thromb Haemostas 2011; 105: 221–231.

9. Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost 2009; 102: 360–370.

10. Šimon J, Rosolová H, Mayer O jr. Základy epidemiologie kardiovaskulárních chorob. Cor Vasa 2008; 50: 87–93.

11. Dahlbäck B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 2008; 112: 19–27.

12. Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemostas 2009; 7(Suppl 1): 301–304.

13. Bertina RM, Rosendaal FR. Venous thrombosis – the interaction of genes and environment. N Engl J Med 1998; 338: 1840–1841.

14. van Boven HH, Vandenbroucke JP, BriĎt E, Rosendaal FR. Gene-gene and gene-environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency. Blood 1999; 94: 2590–2594.

15. 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: 64–67.

16. Poort SR, osendaal FR, eitsma PH, ertina 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: 3698–3703.

17. Gehring NH, Frede U, Neu-Yilik G, Hundsdoerfer P, Vetter B, Hentze MW, Kulozik AE. Increased efficiency of mRNA 3-prime end formation: a new genetic mechanism contributing to hereditary thrombophilia. Nature Genet 2001; 28: 389–392.

18. Eriksson P, Kallin B, van‘t Hooft FM, BĆvenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen–activator inhibitor 1 gene is associated with myocardial infarction. PNAS 1995; 92: 1851–1855.

19. Ridker PM, Miletich JP, Hennekens ChH, Buring JE. Ethnic distribution of Factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA 1997; 277: 1305–1307.

20. Rees DC, Chapman NH, Webster MT, Guerreiro JF, Rochette J, Clegg JB. Born to clot: the European burden. Br J Haematol 1999; 105: 564–566.

21. Miyata T, Kawasaki T, Fujimura H, Uchida K, Tsushima M, Kato H. The prothrombin gene G20210A mutation is not found among Japanese patients with deep vein thrombosis and healthy individuals. Blood Coagul Fibrinolysis 1998; 9: 451–452.

22. Zivelin A, Mor-Cohen R, Kovalsky V, Kornbrot N, Conard J, Peyvandi F, Kyrle PA, Bertina R, Peyvandi F, Emmerich J, Seligsohn U. Prothrombin 20210G-A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago. Blood 2006; 107: 4666–4668.

23. Kjellberg U, van Rooijen M, Bremme K, Hellgren M. Factor V eiden and pregnancy–related complications. Am J Obstet Gynecol 2010; 203: e1–8.

24. Bryce A, Kerlin S,Yan B, Isermann BH, Brandt JT, Sood R, Basson BR, Joyce DE, Weiler H, Dhainaut J-F. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood 2003; 102: 3085–3092.

25. Lucotte G, ercier G. Population genetics of factor V Leiden in Europe. Blood Cells Mol Dis 001; 27: 362–367.

26. Holm J, Zöller B, Berntorp E, Erhardt L, Dahlbäc B. Prevalence of factor V gene mutation amongst myocardial infarction patients and healthy controls is higher in Sweden than in other countries. J Intern Med 1996; 239: 221–226.

27. Bertina RM. The prothrombin 20210 G to A variation and thrombosis. Curr Opin Hematol 998; 5: 339–342.

28. Mazoyer E, Ripoll L, Gueguen R, Tiret L, Collet JP, Sollier CB, Roussi J, Drouet L; for the FITENAT Study Group. Prevalence of factor V Leiden and prothrombin G20210A mutation in a large French population selected for nonthrombotic history: geographical and age distribution. Blood Coagul Fibrinolysis 2009; 20: 503–510.

29. Bauduera FD, Lacombeb D. Minireview. Factor V Leiden, prothrombin 20210A, methylenetetrahydrofolate reductase 677T, and population genetics. Molecular Genetics and Metabolism 2005; 86: 91–99.

30. Lissalde-Lavigne G, Fabbro-Peray P, Cochery-Nouvellon E, Mercier E, Ripart-Neveu S, Balducchi J-P, Daures J-P, Perneger T, Quere I, Dauzat M, Mares P, Gris J-C. Factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case-control ‘NOHA first’ study. J Thromb Haemost 2005; 3: 2178–2184.

31. Sottilotta G, ammď C, urlė G, riana V, atella C, rapani I, Lombardo V. High incidence of factor V Leiden and prothrombin G20210A in healthy southern Italians. Clin Appl Thromb Hemost 009; 15: 356–359.

32. Honzák R. Faktor V Leiden a slovenská populace. Prakt Lék 1999; 12: 845–850.

33. Hoppe B, Tolou F, Dörner T, Kiesewetter H, Salama A. Gene polymorphisms implicated in influencing susceptibility to venous and arterial thromboembolism: frequency distribution in a healthy German population. Thromb Haemost 2006; 96: 465–470.

34. Schwender S, Grossmann R, Keller F. High prevalence of Factor V eiden mutation is detected in a north to south axis through Germany. Journal of Laboratory Medicine 1997; 21: 347–353.

35. Braun A, Muller B, Rosche AA. Population study of the G1691A mutation (R 506 Q, FV eiden) in the human factor V ene that is associated with resistance to activated protein C. Hum Genet 1996; 97: 263–264.

36. Adler G, Parczewski M, Czerska E, Loniewska B, Kaczmarczyk M, Gumprecht J, Grzeszczak W, Szybinska A, Mossakowska M, Ciechanowicz A. An age-related decrease in factor V Leiden frequency among Polish subjects. ournal of Applied Genetics 2010; 51: 337–341.

37. Renner W, Koppel H, Hoffmann Ch, Schallmoser K, Stanger O, Toplak H, Wascher TC, Pilger E. Prothrombin G20210A, factor V eiden, and factor XIII Val34Leu: common mutation of blood coagulation factors and deep vein thrombosis in Austria. Thrombosis Res 2000; 99: 35–39.

38. Matýšková M, Paseka J, Vorlová Z, Bulíková A, Hrachovinová I, Janků L. Prevalence of factor V eiden mutation in healthy women. In: I.Scharrer, W.Schramm eds.: 29. Hämophilie Symposion Hamburg 1998. Berlin – Heidelberg: Springer Verlag 1999; 309–311.

39. Dulíček P, Chrobák L, Kalousek I, Pešanová L, Pecka M, Stránský P. Is Factor V eiden associated with an increased risk for fetal loss ? In: I.Scharrer, W.Schramm eds. 30th Hemophilia Symposium Hamburg 1999. Berlin – Heidelberg: Springer Verlag 2001; 217– 221.

40. Hrachovinová I, Vorlová Z, Matýšková M, Janků L. Thrombotic risk of the prothrombin gene G20210A mutation and clinical features of thrombophilia in 50 carriers of mutation. Thromb Haemostas 1999 (Suppl); Abstract No 2060, XVIIth Congress of the ISTH, Washington D.C., USA, s. 652.

41. Paseka J, Unzeitig V, Cibula D, Buliková A, Matýškova M, Chroust K. Leidenská mutace faktoru V u uživatelek hormonální antikoncepce. Čes Gynekol 2000; 65: 156–159.

42. Raušová E, Hadačová I, Macek M. Hereditární trombofilie – jeden z odelů molekulární mediciny. Klin Biochem Metab 2005; 13: 68–76.

43. Asselbergs FW, Williams SM, Hebert PR, Coffey CS, Hillege HL, Navis G, Vaughan DE, van Gilst WH, Moore JH. Gender-specific correlations of plasminogen activator inhibitor-1 and tissue plasminogen activator levels with cardiovascular disease-related traits. J Thromb Haemost 2007; 5: 313–320.

44. Bucková D, Izakovicová-Hollá L, Vácha J. Polymorphism 4G/5G in the plasminogen activator inhibitor-1 (PAI-1) gene is associated with IgE-mediated allergic diseases and asthma in the Czech population. Allergy 2002; 57: 446–448.

45. Ma Z, Paek D, Oh CK. Plasminogen activator inhibitor-1 and asthma: role in the pathogenesis and molecular regulation. Clin Exp Allergy 2009; 39: 1136–1144.

46. Kowal K, Bodzenta-Lukaszyk A, Pampuch A, Szmitkowski M, Zukowski S, Donati MB, Iacoviello L. Analysis of -675 4 g/5 G SERPINE1 and C-159T CD14 polymorphisms in house dust mite-allergic asthma patients. J Investig Allergol Clin Immunol 2008; 18: 284–292.

47. Hubáček JA, Staněk V, Gebauerová M, Pilipčincová A, Poledne R, Aschermann M, Skalická H, Matoušková J, Kruger A, Pěnička M, Hrabáková H, Veselka J, Hájek P, Lánská V, Adámková V, Pit‘ha J. Lack of an association between connexin-37, stromelysin-1, plasminogen activator-inhibitor type 1 and lymphotoxin-alpha genes and acute coronary syndrome in Czech Caucasians. Exp Clin Cardiol 2010; 15: e52–e56.

48. Tatarskyy P, Kucherenko A, Livshits L. Allelic polymorphism of F2, F5 and MTHFR genes in population of Ukraine. Tsitol Genet 2010; 44: 3–8.

49. Herrmann FH, Koesling M, Schroder W, Altmann R, Jimenéz Bonilla R, Lopaciuk S, Perez-Requejo JL, Singh JR. Prevalence of factor V eiden mutation in various population. Genet Epidemiol 1997; 14: 403–411.

50. Irani-Hakime N, Tamim H, Elias G, Finan RR, Daccache JL, Almawi WY. High Prevalence of Factor V utation (Leiden) in the Eastern Mediterranean. Clinical Chemistry 2000; 46: 134–136.

51. Wu O, Robertson L, Twaddle S, t al. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS). Health Technol Assess 2006; 10: 1–110.

52. De Stefano V, Martinelli I, Mannucci PM, Paciaroni K, Chiusolo P, Casorelli I, Rossi E, Leone G. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. New Eng J Med 1999; 341: 801–806.

53. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Collaborators: Berg AO, Botkin J, Calonge N, Campos–Outcalt D, Haddow JE, Hayes M, Kaye C, Klein RD, Offit K, Pauker SG, Piper M, Richards CS, Scott JA, Strickland OL, Teutsch S, Veenstra DL. Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members. Genet Med 2011; 13: 67–76.

54. Marchiori A, Mosena L, Prins MH, Prandoni P. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies. Haematologica 2007; 92: 1107–1114.

55. Kyrle PA, Rosendaal FR, Eichinger S. Risk assessment for recurrent venous thrombosis. Lancet 2010; 376(9757): 2032–2039.

56. Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation 2010; 121: 1630–1636.

57. Tsantes AE, Nikolopoulos GK, Bagos PG, Bonovas S, Kopterides P, Vaiopoulos G. The effect of the plasminogen activator inhibitor–1 4G/5G polymorphism on the thrombotic risk. Thromb Res 2008; 122: 736–742.

58. Stegnar M, Uhrin P, Peternel P, Mavri A, Salobir-Pajnic B, Stare J, Binder BR. The 4G/5G sequence polymorphism in the promoter of plasminogen activator inhibitor-1 (PAI-1) gene: relationship to plasma PAI-1 level in venous thromboembolism. Thromb Haemost 1998; 79: 975–979.

59. Seguí R, Estellés A, Mira Y, EspaĖa F, Villa P, Falcó C, Vayá A, Grancha S, Ferrando F, Aznar J. PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects. Br J Haematol 2000; 111: 122–128.

60. Sartori MT, Danesin C, Saggiorato G, Tormene D, Simioni P, Spiezia L, Patrassi GM, Girolami A. The PAI-1 gene 4G/5G polymorphism and deep vein thrombosis in patients with inherited thrombophilia. Clin Appl Thromb Hemost 2003; 9: 299–307.

61. Bern MM, McCarthy N. Failure to lyse venous thrombi because of elevated plasminogen activator inhibitor 1 (PAI-1) and 4G polymorphism of its promotor genome (The PAI–1/4G Syndrome). Clin Appl Thromb Hemost 2010; 16: 574–578.

62. Kruithof EKO. Regulation of plasminogen activator inhibitor type I gene expression by inflammatory mediators and statins. Thromb Haemost 2008; 100: 969–975.

63. Kvasnička J. Dědičné trombofilie – doporučení k rovádění genetických testů v linické praxi. Čas Lék čes 2010; 149: 468–471.

64. Kitsios GD, Dahabreh IJ, Trikalinos TA, Schmid CH, Huggins GS, Kent DM. Heterogeneity of the phenotypic definition of coronary artery disease and its impact on genetic association studies. Circ Cardiovasc Genet 2011; 4: 58–67.

65. Bentley P, Peck G, Smeeth L, Whittaker J, Sharma P. Causal relationship of susceptibility genes to ischemic stroke: comparison to ischemic heart disease and biochemical determinants. Plos One 2010; 5: e9136.

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