Mutácia protrombínového génu 20210A v slovenskej populácii


Autoři: Juraj Chudej;  Ivana Plameňová
Působiště autorů: Department of Haematology and Transfusion Medicine, National Centre for Haemostasis and Thrombosis, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovakia
Vyšlo v časopise: Vnitř Lék 2016; 62(4): 281-286
Kategorie: Původní práce

Souhrn

Úvod:
Mutácia faktora V Leiden (FVL) spolu a mutácia G20210A v protrombínovom géne (PTM) patria medzi 2 najčastejšie genetické polymorfizmy, ktoré predispozíciou pre rozvoj prevej epizódy venózneho tromboemblizmu (VTE). PTM sa vyskytuje v 2 % belošskej populácie. Hlavným cieľom tejto práce bolo zistiť prevalenciu PTM v populácii pacientov s anamnézou trombotickej príhody vs. zdravých kontrolách.

Materiál a metódy:
Za účelom posúdenie prítomnosti PTM bola realizovaná PCR analýza z DNA extrahovanej z periférnych leukocytov.

Výsledky:
Do štúdie bolo zaradených 2 274 pacientov, z nich 157 (6,9 %) malo prítomnú PTM. PTM mutácia bola prítomná u 2,6 % kontrol z celkového počtu 303 dobrovoľníkov. Analyzovali sme klinickú manifestáciu PTM. Pozorovali sme 123 venóznych trombóz, 46 artériových trombóz a 14 opakovaných spontánnych potratov. V tomto článku sme ďalej analyzovali ďalšie možné rizikové faktory rozvoja trombózy u pacientov s prítomnou PTM.

Záver:
Podľa našich vedomostí je toto najväčšia epidemiologická štúdia zameraná na výskyt PTM v strednej Európe. Za použitia štatistickej analýzy sme zistili relatívne vysoký výskyt PTM v populácii pacientov s anamnézou trombózy (6,9 %), ale aj u zdravých kontrol (2,6 %). Riziko trombózy je nezávislé od veku a pohlavia. Štúdia zároveň ukázala pomerne častý výskyt dvojitej prítomnosti PTM a FVL.

Kľúčové slová:
mutácia – populácia – protrombín – trombóza


Zdroje

1. Chang MH, Lindegren ML, Butler MA et al. Prevalence in the United States of selected candidate gene variants: Third National Health and Nutrition Examination Survey, 1991–1994. Am J Epidemiol 2009; 169(1): 54–66.

2. Degen SJ, Davie EW. Nucleotide sequence of the gene for human prothrombin. Biochemistry 1987; 26(19): 6165–6177.

3. Poort SR, Rosendaal FR, Reitsma PH et al. 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(10): 3698–3703.

4. Simioni P, Tormene D, Manfrin D et al. Prothrombin antigen levels in symptomatic and asymptomatic carriers of the 20210A prothrombin variant. Br J Haematol 1998; 103(4): 1045–1050.

5. Kyrle PA, Mannhalter C, Beguin S et al. Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene. Arterioscler Thromb Vasc Biol 1998; 18(8):1287–1291.

6. Zawadzki C, Gaveriaux V, Trillot N et al. Homozygous G20210A transition in the prothrombin gene associated with severe venous thrombotic disease: two cases in a French family. Thromb Haemost 1998; 80(6): 1027–1028.

7. Morange PE, Barthet MC, Henry M et al. A three-generation family presenting five cases of homozygosity for the 20210 G to A prothrombin variant. Thromb Haemost 1998; 80(5): 859–860.

8. Eikelboom JW, Ivey L, Ivey J et al. Familial thrombophilia and the prothrombin 20210A mutation: association with increased thrombin generation and unusual thrombosis. Blood Coagul Fibrinolysis 1999; 10(1): 1–5.

9. Corral J, Zuazu-Jausoro I, Rivera J et al. Clinical and analytical relevance of the combination of prothrombin 20210A/A and factor V Leiden: results from a large family. Br J Haematol 1999; 105(2): 560–563.

10. Zivelin A, Rosenberg N, Faier S et al. A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene. Blood 1998; 92(4): 1119–1124.

11. Ridker PM, Hennekens CH, Miletich JP. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation 1999; 99(8): 999–1004.

12. Kapur RK, Mills LA, Spitzer SG et al. A prothrombin gene mutation is significantly associated with venous thrombosis. Arterioscler Thromb Vasc Biol 1997; 17(11): 2875–2879.

13. Margaglione M, Brancaccio V, Giuliani N et al. Increased risk for venous thrombosis in carriers of the prothrombin G–>A20210 gene variant. Ann Intern Med 1998; 129(2): 89–93.

14. Alhenc-Gelas M, Arnaud E, Nicaud V et al. Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes. Thromb Haemost 1999; 81(4): 506–510.

15. Nowak-Gottl U, Junker R, Kreuz W et al. (Childhood Thrombophilia Study Group). Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood 2001; 97(4): 858–862.

16. Arruda VR, Annichino-Bizzacchi JM, Goncalves MS et al. Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease. Thromb Haemost 1997; 78(6): 1430–1433.

17. Gurgey A, Kudayarov DK, Tuncer M et al. The factor V Leiden and prothrombin G20210A mutations in Kirghiz population. Thromb Haemost 2000; 84(2): 356.

18. Dilley A, Austin H, Hooper WC et al. Prevalence of the prothrombin 20210 G-to-A variant in blacks: infants, patients with venous thrombosis, patients with myocardial infarction, and control subjects. J Lab Clin Med 1998; 132(6): 452–455.

19. Ho CH. Prevalence of prothrombin 20210A allele and methylenetetrahydrofolate reductase C677T genetic mutations in the Chinese population. Ann Hematol 2000; 79(5): 239–242.

20. Vandenbroucke JP, Rosing J, Bloemenkamp KW et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 344(20): 1527–1535.

21. Martinelli I, Taioli E, Bucciarelli P et al. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc Biol 1999; 19(3): 700–703.

22. Gerhardt A, Scharf RE, Beckmann MW et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000; 342(6): 374–380.

23. Sokol J, Biringer K, Skerenova M et al. Platelet aggregation abnormalities in patients with fetal losses: the GP6 gene polymorphism. Fertil Steril 2012; 98(5): 1170–1174.

24. Sokol J, Biringer K, Skerenova M et al. Different models of inheritance in selected genes in patients with sticky platelet syndrome and fetal loss. Semin Thromb Hemost 2015; 41(3): 330–335.

25. Sokol J, Biringer K, Skerenova M et al. Activity of coagulation factor XI in patients with spontaneous miscarriage: The presence of risk alleles. J Obstet Gynaecol 2015; 35(6): 621–624.

26. Šimonová R, Bartosová L, Chudy P et al. Nine kindreds of familial sticky platelet syndrome phenotype. Clin Appl Thromb Hemost 2013; 19(4): 395–401.

27. Francs F, Portols O, Gabriel F et al. Factor V Leiden (G1691A) and prothrombin-G20210A alleles among patients with deep venous thrombosis and in the general population from Spain. Rev Med Chil 2006; 134(1): 13–20.

28. Alvarez A, Barroso A, Robledo M et al. Prevalence of Factor V Leiden and the G20210A mutation of the prothrombin gene in a random group of patients with thrombotic episodes. Sangre (Barc) 1999; 44(1): 7–12.

29. Souto JC, Coll I, Llobet D et al. The prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemost 1998; 80(3): 366–369.

30. Leroyer C, Mercier B, Oger E et al. Prevalence of 20210 A allele of the prothrombin gene in venous thromboembolism patients. Thromb Haemost 1998; 80(1): 49–51.

31. Mazoyer E, Ripoll L, Gueguen R et al. (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(7): 503–510.

32. Reny JL, Alhenc-Gelas M, Fontana P et al. The factor II G20210A gene polymorphism, but not factor V Arg506Gln, is associated with peripheral arterial disease: results of a case-control study. J Thromb Haemost 2004; 2(8): 1334–1340.

33. Martinelli I, Bucciarelli P, Margaglione M et al. The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both. Br J Haematol 2000; 111(4): 1223–1239.

34. de Moerloose P, Reber G, Perrier A et al. Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism. Br J Haematol 2000; 110(1): 125–129.

35. Sottilotta G, Mamm C, Furl G et al. High incidence of factor V Leiden and prothrombin G20210A in healthy southern Italians. Clin Appl Thromb Hemost 2009; 15(3): 356–359.

36. Tosetto A, Missiaglia E, Frezzato M et al. The VITA project: prothrombin G20210A mutation and venous thromboembolism in the general population. Thromb Haemost 1999; 82(5): 1395–1398.

37. Bedencic M, Bozic M, Peternel P et al. Major and potential prothrombotic genotypes in patients with venous thrombosis and in healthy subjects from Slovenia. Pathophysiol Haemost Thromb 2008; 36(2): 58–63.

38. Zerjavic K, Zagradisnik B, Stangler Herodez S et al. Is the JAK2 V617F mutation a hallmark for different forms of thrombosis? Acta Haematol 2010; 124(1): 49–56.

39. Jukic I, Bingulac-Popovic J, Dogic V et al. ABO blood groups and genetic risk factors for thrombosis in Croatian population. Croat Med J 2009; 50(6): 550–558.

40. Herak DC, Antolic MR, Krleza JL et al. Inherited prothrombotic risk factors in children with stroke, transient ischemic attack, or migraine. Pediatrics 2009; 123(4): e653-e660. Dostupné z DOI: <http://dx.doi.org/10.1542/peds.2007–3737>.

41. Eterović D, Titlić M, Culić V et al. Lower contribution of factor V Leiden or G202104 mutations to ischemic stroke in patients with clinical risk factors: pair-matched case-control study. Clin Appl Thromb Hemost 2007; 13(2): 188–193.

42. Coen D, Zadro R, Honović L et al. Prevalence and association of the factor V Leiden and prothrombin G20210A in healthy subjects and patients with venous thromboembolism. Croat Med J 2001; 42(4): 488–492.

43. Djordjevic V, Rakicevic LJ, Mikovic D et al. Prevalence of factor V leiden, factor V cambridge, factor II G20210A and methylenetetrahydrofolate reductase C677T mutations in healthy and thrombophilic Serbian populations. Acta Haematol 2004; 112(4): 227–229.

44. Foka ZJ, Lambropoulos AF, Makris PE et al. High frequency of factor V Leiden and prothrombin G20210A mutations in Greek hemophiliacs. J Thromb Haemost 2003; 1(5): 1116–1167.

45. Hatzaki A, Anagnostopoulou E, Metaxa-Mariatou V et al. The impact of heterozygosity for the factor V Leiden and factor II G20210A mutations on the risk of thrombosis in Greek patients. Int Angiol 2003; 22(1): 79–82.

46. Zalavras CG, Giotopoulou S, Dokou E et al. Prevalence of the G20210A prothrombin gene mutation in Northwestern Greece and association with venous thromboembolism. Int Angiol 2003; 22(1): 55–57.

47. Antoniadi T, Hatzis T, Kroupis C et al. Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in a Greek population of blood donors. Am J Hematol 1999; 61(4): 265–267.

48. Tug E, Aydin H, Kaplan E et al. Frequency of genetic mutations associated with thromboembolism in the Western Black Sea Region. Intern Med 2011; 50(1): 17–21.

49. Altinisik J, Ates O, Ulutin T et al. Factor V Leiden, prothrombin G20210A, and protein C mutation frequency in Turkish venous thrombosis patients. Clin Appl Thromb Hemost 2008; 14(4): 415–420.

50. Irdem A, Devecioglu C, Batun S et al. Prevalence of factor V Leiden and prothrombin G20210A gene mutation. Saudi Med J 2005; 26(4): 580–583.

51. Xenophontos SL, Hadjivassiliou M, Ayrton N et al. Spectrum and prevalence of prothrombotic single nucleotide polymorphism profiles in the Greek Cypriot population. Int Angiol 2002; 21(4): 322–329.

52. Angelopoulou K, Nicolaides A, Constantinou DC. Prevalence of genetic mutations that predispose to thrombophilia in a Greek Cypriot population. Clin Appl Thromb Hemost 2000; 6(2): 104–107.

53. Barcellona D, Fenu L, Cauli C et al. Allele 4G of gene PAI-1 associated with prothrombin mutation G20210A increases the risk for venous thrombosis. Thromb Haemost. 2003; 90(6): 1061–1064.

54. Hillarp A, Zoller B, Svensson PJ et al. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost l997; 78(3): 990–992.

55. Kvasnička J. Doporučený postup pro indikaci molekulárně genetických vyšetření v rámci diagnostiky trombofilních stavů v žilním systému. Vnitř Lék 2010; 56(12): 1251.

56. Dulíček P. Trombofilní stavy. Vnitř Lék 2005; 91(7–8): 819–825.

57. Piťha J, Auzký O, Roztočil K. Co mají společného žilní a tepenná onemocnéní? Vnitř Lék 2014; 60(11): 985–989.

58. Dulíček P, Vodičková L, Malý J et al. ,,Nejasná” príčina vzniku recidívy venózneho tromboembolizmu. Vnitř Lék 2006; 52(1): 87–88.

59. Bauer KA. The thrombophilias: well-defined risk factors with uncertain therapeutic implications. Ann Int Med 2001; 135(5): 367–373.

60. Walker ID, Greaves M, Preston FE. Investigation and management of heritable thrombophilia. Br J Haematol 2001; 114(3): 512–528.

61. Rosendaal FR. Venous thrombosis: multicausal disease. Lancet 1999; 353(9159): 1167–1173.

62. Dahl OE. Mechanisms of hypercoagulability. Thromb Haemost 1999; 82(2): 902–906.

Štítky
Diabetologie Endokrinologie Interní lékařství

Článek vyšel v časopise

Vnitřní lékařství

Číslo 4

2016 Číslo 4

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Přihlášení
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se