Investigation of the Frequency of Thrombophilic Gene Mutations in Patients with Venous Thromboembolism in Eastern Turkey

Yıl 2023, Cilt: 33 Sayı: 3, 268 - 273, 30.06.2023

Muhammed Ertugrul Egin , Zülfinaz Betül Çelik , Ümit Kervan , Mehmet Karahan , Abdulgani Tatar

https://doi.org/10.54005/geneltip.1196430

Öz

Objectives: Polymorphisms in the thrombophilia genes such as Factor V Leiden (FVL), Prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR) cause genetic predisposition to thrombophilia. The regional incidence of these polymorphisms varies. The aim of our study is to evaluate the regional frequency of the most common single nucleotide polymorphisms of these thrombophilia genes.
Methods: In this retrospective study, patients diagnosed with VTE in our center were included in the study. The presence of FVL, Prothrombin G20210A, MTHFR C677T, MTHFR A1298C, plasminogen activator inhibitor (PAI)-1, β-Fibrinogen, Factor XIIIA (V34L) and Glycoprotein IIIA (L33P) were investigated in blood samples obtained from the patients, and the association of genotype disorders was also evaluated.
Results: Eight genotypes were analyzed in 2000 patients whose thrombophilia panel was studied in our clinic. The frequency of heterozygosity for the Factor II G20210A polymorphisms was 4,6%, the homozygosity for the Factor V Leiden polymorphism was 0,4%, for MTHFR C677T 7,6% , for MTHFR A1298C 48,1% and 15,7% , for PAI-1 38,8% and 13% , for β-Fibrinogen 30,3% and 4%, for Factor XIIIA (V34L) 23,3% and 2,4% and for Glycoprotein IIIA (L33P) 17,7% and 1,5% respectively.
Conclusions: Factor V Leiden and Factor II (Prothrombin) G20210A mutations were found at a higher rate in our region compared to other regions in the west.

Anahtar Kelimeler

thrombophilia, venous thromboembolism, gene mutation

Destekleyen Kurum

none

Proje Numarası

none

Teşekkür

none

Türkiye'nin Doğu Anadolu Bölgesi'nde Venöz Tromboembolizm olan Hastalarda Trombofilik Gen Mutasyonlarının Sıklığının Araştırılması

Öz

Amaç: Faktör V Leiden (FVL), Protrombin G20210A ve metilentetrahidrofolat redüktaz (MTHFR) gibi trombofili genlerindeki polimorfizmler, trombofili için genetik yatkınlığa neden olur. Bu polimorfizmlerin bölgesel insidansı değişiklik gösterebilmektedir. Çalışmamızın amacı, bu trombofili genlerinin en sık görülen tek nükleotid polimorfizmlerinin bölgesel sıklığını değerlendirmektir.
Yöntemler: Retrospektif olarak dizayn edilen bu çalışmada merkezimizde VTE tanısı alan hastalar araştırmaya dahil edildi. Hastalardan elde edilen kan örnekleri ile FVL, Protrombin G20210A, MTHFR C677T, MTHFR A1298C, plazminojen aktivatör inhibitörü (PAI)-1, β-Fibrinojen, Faktör XIIIA (V34L) ve Glikoprotein IIIA (L33P) varlığı araştırıldı ve genotip bozukluklarının birlikteliği de ayrıca değerlendirildi.
Bulgular: Kliniğimizde trombofili paneli çalışılan 2000 hastada sekiz genotip analiz edildi. Faktör II G20210A polimorfizmleri için heterozigotluk sıklığı %4,6, Faktör V Leiden polimorfizmi için homozigotluk %0,4, MTHFR C677T için %7,6, MTHFR A1298C için %48,1 ve %15,7, PAI-1 için %38,8 ve %13 , β-Fibrinojen için %30,3 ve %4, Faktör XIIIA (V34L) için %23,3 ve %2,4 ve Glikoprotein IIIA (L33P) için % 17,7 ve %1,5 bulunmuştur.
Sonuç: Bölgemizde Faktör V Leiden ve Faktör II (Protrombin) G20210A mutasyonları batıdaki diğer bölgelere göre daha yüksek oranda bulundu.

Anahtar Kelimeler

trombofili, venöz tromboembolizm, gen mutasyonu

Proje Numarası

none

Kaynakça

• 1. Atahan E, Çağlar E, Şarkış C, Uğurlu S. Venöz tromboemboli ve kalıtsal trombofili. Turkish J Thorac Cardiovasc Surg. 2009;17(4):302-11.
• 2. Williamson D, Brown K, Luddington R, Baglin C, Baglin T. Factor V Cambridge: a new mutation (Arg306-->Thr) associated with resistance to activated protein C. Blood. 1998;91(4):1140-4.
• 3. De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood. 1996;87(9):3531-44.
• 4. Zivelin A, Griffin JH, Xu X, Pabinger I, Samama M, Conard J, et al. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood. 1997;89(2):397-402.
• 5. Kabukcu S, Keskin N, Keskin A, Atalay E. The frequency of factor V Leiden and concomitance of factor V Leiden with prothrombin G20210A mutation and methylene tetrahydrofolate reductase C677T gene mutation in healthy population of Denizli, Aegean region of Turkey. Clin Appl Thromb Hemost. 2007;13(2):166-71.
• 6. Mazoyer E, Ripoll L, Gueguen R, Tiret L, Collet JP, dit Sollier CB, et al. 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):503-10.
• 7. Fujimura H, Kambayashi J-i, Monden M, Kato H, Miyata T. Coagulation factor V Leiden mutation may have a racial background. Thrombosis and haemostasis. 1995;74(11):1381-2.
• 8. Herrmann FH, Koesling M, Schroder W, Altman R, Jimenez Bonilla R, Lopaciuk S, et al. Prevalence of factor V Leiden mutation in various populations. Genet Epidemiol. 1997;14(4):403-11.
• 9. Akar N, Akar E, Dalgin G, Sozuoz A, Omurlu K, Cin S. Frequency of Factor V (1691 G --> A) mutation in Turkish population. Thromb Haemost. 1997;78(6):1527-8.
• 10. Ozbek U, Tangun Y. Frequency of factor V Leiden in Turkey. Int J Hematol. 1996;64(3-4):291-2.
• 11. Vurkun M, Vural O, Demir M, Turgut B, Gurgey A, Parlak H, et al. The Prevalence of Activated Protein C Resistance and F V Leiden in Healthy Population of Edirne, Turkey. Turk J Haematol. 2002;19(2):287-91.
• 12. Özen F, Koçak N, Yıldırım ME, Özdemir Ö. Sivas populasyonunda faktör V genin leiden (G1691a) ve Hr2 (A4070g) polimorfizmleri. Journal of Turgut Ozal Medical Center. 2009;16(3):179-84.
• 13. Simioni P, Prandoni P, Lensing AW, Manfrin D, Tormene D, Gavasso S, et al. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis. Blood. 2000;96(10):3329-33.
• 14. Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N, Johnsson H. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation. Thromb Haemost. 1999;81(5):684-9.
• 15. Akar N, Misirlioglu M, Akar E, Avcu F, Yalcin A, Sozuoz A. Prothrombin gene 20210 G-A mutation in the Turkish population. Am J Hematol. 1998;58(3):249.
• 16. Ayyildiz O, Kalkanli S, Batun S, Aybak M, Isikdogan A, Tiftik N, et al. Prothrombin G20210A gene mutation with LightCycler polymerase chain reaction in venous thrombosis and healthy population in the southeast of Turkey. Heart and Vessels. 2004;19(4):164-6.
• 17. Oztuzcu S, Ergun S, Ulaşlı M, Nacarkahya G, Iğci YZ, Iğci M, et al. Evaluation of Factor V G1691A, prothrombin G20210A, Factor XIII V34L, MTHFR A1298C, MTHFR C677T and PAI-1 4G/5G genotype frequencies of patients subjected to cardiovascular disease (CVD) panel in south-east region of Turkey. Molecular biology reports. 2014;41(6):3671-6.
• 18. Dölek B, Eraslan S, Eroğlu S, Kesim BE, Ulutin T, Yalçıner A, et al. Molecular analysis of factor V Leiden, factor V Hong Kong, factor II G20210A, methylenetetrahydrofolate reductase C677T, and A1298C mutations related to Turkish thrombosis patients. Clinical and Applied Thrombosis/Hemostasis. 2007;13(4):435-8.
• 19. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111-3.
• 20. van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998;62(5):1044-51.
• 21. Bertina R. Hereditary protein S deficiency. Pathophysiology of Haemostasis and Thrombosis. 1985;15(4):241-6. 22. Güuleçl S, Aras Ö, Akar E, Tutar E, Omurlo K, Avci F, et al. Methylenetetrahydrofolate reductase gene polymorphism and risk of premature myocardial infarction. Clinical cardiology. 2001;24(4):281-4.
• 23. Sazci A, Ergul E, Kaya G, Kara I. Genotype and allele frequencies of the polymorphic methylenetetrahydrofolate reductase gene in Turkey. Cell Biochemistry and Function: Cellular biochemistry and its modulation by active agents or disease. 2005;23(1):51-4.
• 24. Kim KN, Kim KM, Kim BT, Joo NS, Cho DY, Lee DJ. Relationship of plasminogen activator inhibitor 1 gene 4G/5G polymorphisms to hypertension in Korean women. Chin Med J (Engl). 2012;125(7):1249-53.
• 25. Mahfouz RA, Sabbagh AS, Shammaa DM, Otrock ZK, Zaatari GS, Taher AT. Factor XIII gene V34L mutation in the Lebanese population: Another unique feature in this community? Molecular biology reports. 2008;35(3):375-8.
• 26. Prandini M, Denarier E, Frachet P, Uzan G, Marguerie G. Isolation of the human platelet glycoprotein IIb gene and characterization of the 5′ flanking region. Biochemical and biophysical research communications. 1988;156(1):595-601.
• 27. Newman PJ, Derbes RS, Aster RH. The human platelet alloantigens, PlA1 and PlA2, are associated with a leucine33/proline33 amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing. The Journal of clinical investigation. 1989;83(5):1778-81.