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…


Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Zánětlivá bolest zad a axiální spondylartritida – Diagnostika a referenční strategie
nový kurz
Autoři: MUDr. Monika Gregová, Ph.D., MUDr. Kristýna Bubová

Inhibitory karboanhydrázy v léčbě glaukomu
Autoři: as. MUDr. Petr Výborný, CSc., FEBO

Příběh jedlé sody
Autoři: MUDr. Ladislav Korábek, CSc., MBA

Krvácení v důsledku portální hypertenze při jaterní cirhóze – od pohledu záchranné služby až po závěrečný hepato-gastroenterologický pohled
Autoři: PhDr. Petr Jaššo, MBA, MUDr. Hynek Fiala, Ph.D., prof. MUDr. Radan Brůha, CSc., MUDr. Tomáš Fejfar, Ph.D., MUDr. David Astapenko, Ph.D., prof. MUDr. Vladimír Černý, Ph.D.

Rozšíření možností lokální terapie atopické dermatitidy v ordinaci praktického lékaře či alergologa
Autoři: MUDr. Nina Benáková, Ph.D.

Všechny kurzy
Kurzy Doporučená témata Časopisy
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