Kağan KAMAŞAK, Zeynep YEĞİN, İBRAHİM HALİL YILDIRIM

Nöral Tüp Defektlerinde Duyarlılık Oluşturan Risk Faktörleri Olarak Faktör V ve MTHFR Genlerinin Analizi: Türkiye'den Bir Vaka-Kontrol Çalışması

Amaç: Bu çalışma konjenital olmayan nöral tüp defektlerine moleküler bir perspektif sunmayı ve geleceğe yönelik önleyici bireyselleştirilmiş tıp stratejileri geliştirmeyi hedeflemiştir. Üç genetik varyasyon; Factor V Leiden (FVL) (rs6025), MTHFR A1298C (rs1801131) ve MTHFR C677T (rs1801133) bu varyasyonların potansiyel kalıtımsal etkilerini daha iyi analiz etmek için hem anneleri hem de çocukları içeren bir Türk kohortunda araştırılmıştır.

Anahtar Kelimeler:

Factor V Leiden, Nöral tüp defektleri, genetik assosiasyon, risk faktörleri, 5-10-methylenetetrahydrofolate reductase (MTHFR)

ANALYSIS OF FACTOR V AND MTHFR GENES AS RISK FACTORS CONSTITUTING SUSCEPTIBILITY TO NEURAL TUBE DEFECTS: A CASE-CONTROL STUDY FROM TURKEY

Objective: This study targeted to bring a molecular perspective to occult neural tube defects and thus develop future preventive personalized medicine strategies. The roles of three genetic variations namely Factor V Leiden (FVL) (rs6025), MTHFR A1298C (rs1801131), and MTHFR C677T (rs1801133) were investigated in a Turkish cohort including both the mothers and children to better analyze the potential inherited effects of these variations.

Keywords:

Neural tube defects (NTDs) genetic association, risk factors, , Factor V Leiden, 5-10-methylenetetrahydrofolate reductase (MTHFR),

PDF

___

1. Paul S, Sadhukhan S, Munian D, Bankura B. Association of FOLH1, DHFR, and MTHFR gene polymorphisms with susceptibility of neural tube defects: A case control study from Eastern India. Birth Defects Research. 2018;110(14):1129-38.
2. Cai CQ, Fang YL, Shu JB, Zhao LS, Zhang RP, Cao LR et al. Association of neural tube defects with maternal alterations and genetic polymorphisms in one-carbon metabolic pathway. Ital J Pediatr. 2019;45(1):37.
3. Liu J, Zhang Y, Jin L, Li G, Wang L, Bao Y et al. Variants in maternal COMT and MTHFR genes and risk of neural tube defects in offspring. Metab Brain Dis. 2015;30(2):507-13.
4. Fang Y, Zhang R, Zhi X, Zhao L, Cao L, Wang Y et al. Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern China. Childs Nerv Syst. 2018;34(4):725-9.
5. Elwood JM, Little J, Elwood JH. Epidemiology and control of neural tube defects. 1st ed. Oxford (UK). Oxford University Press, 1992.
6. Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWRRecomm Rep. 1992;41(RR-14):1-7.
7. Helgadottir LB, Skjeldestad FE, Jacobsen AF, Sandset PM, Jacobsen EM. The association of inherited thrombophilia and intrauterine fetal death: a case-control study. Blood Coagul Fibrinolysis. 2011;22(8):651-6.
8. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG et al. Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat Genet. 1994;7(2):195-200.
9. Mahmutbegović E, Marjanović D, Medjedović E, Mahmutbegović N, Dogan S, Valjevac A et al. Prevalence of F5 1691G>A, F2 20210G>A, and MTHFR 677C>T polymorphisms in Bosnian women with pregnancy loss. Bosn J Basic Med Sci. 2017;17(4):309-14.
10. Ornstein DL and Cushman M. Cardiology patient page. Factor-V Leiden. Circulation. 2003;107(15):e94-7.
11. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215.
12. Beauchamp NJ, Daly ME, Hampton KK, Cooper PC, Preston E. High prevalence of a mutation in the factor V gene within the UK population: relationship to activated protein C resistance and familial thrombosis. Hypertension. 1994;88(1):219-22.
13. Goyette P, Frosst P, Rosenblatt DS, Rozen R. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet. 1995;56(5):1052-9.
14. Van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK et al. A second mutation in the MTHFR gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998;62(5):1044 -51.
15. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H et al. Mutation in blood coagulation factor-V associated with resistance to activated protein C. Nature. 1994;369(6475):64-7.
16. Ibrahim-Kosta M, Suchon P, Couturaud F, Smadja D, Olaso R, Germain M et al. Minor allele of the factor-V K858R variant protects from venous thrombosis only in non-carriers of factor-V Leiden mutation. Sci Rep. 2019;9(1):3750.
17. Yalcintepe S, Ozdemir O, Hacivelioglu SO, Akurut C, Koc E, Uludag A et al. Multiple Inherited Thrombophilic Gene Polymorphisms in Spontaneous Abortions in Turkish Population. Int J Mol Cell Med. 2015;4(2):120-7.
18. Udry S, Aranda FM, Latino JO, de Larrañaga GF. Paternal factor V Leiden and recurrent pregnancy loss: a new concept behind fetal genetics? Reply. J Thromb Haemost. 2014;12(10):1759-60.
19. Ahmed NA, Adam I, Elzaki SEG, Awooda HA, Hamdan HZ. Factor-V Leiden G1691A and prothrombin G20210A polymorphisms in Sudanese women with preeclampsia, a case -control study. BMC Med Genet. 2019;20(1):2.
20. Dudding T, Heron J, Thakkinstian A, Nurk E, Golding J, Pembrey M et al. Factor V Leiden is associated with pre-eclampsia but not with fetal growth restriction: a genetic association study and meta-analysis. J Thromb Haemost. 2008;6(11):1869-75.
21. Dissanayake VH, Sirisena ND, Weerasekera LY, Gammulla CG, Seneviratne HR, Jayasekara RW. Candidate gene study of genetic thrombophilic polymorphisms in pre-eclampsia and recurrent pregnancy loss in Sinhalese women. J Obstet Gynaecol Res. 2012;38(9):1168-76.
22. Said JM, Brennecke SP, Moses EK, Walker SP, Borg AJ, Williams JT et al. Ethnic differences in the prevalence of inherited thrombophilic polymorphisms in an asymptomatic Australian prenatal population. Hum Biol. 2006;78(4):403-12.
23. Ryckman KK, Dagle JM, Kelsey K, Momany AM, Murray JC. Replication of genetic associations in the inflamation, complement, and coagulation pathways with intraventricular hemorrhage in LBW preterm neonates. Pediatr Res. 2011;70(1):90-5.
24. Aydin H, Arisoy R, Karaman A, Erdoğdu E, Çetinkaya A, B Geçkinli B et al. Evaluation of maternal serum folate, vitamin B12, and homocysteine levels and factor V Leiden, factor II g.20210G>A, and MTHFR variations in prenatally diagnosed neural tube defects. Turk J Med Sci. 2016;46(2):489-94.
25. Yu Y, Wang F, Bao Y, Lu X, Quan L, Lu P. Association between MTHFR gene polymorphism and NTDs in Chinese Han population. Int J Clin Exp Med. 2014;7(9):2901-6.
26. Dutta HK, Borbora D, Baruah M, Narain K. Evidence of gene-gene interactions between MTHFD1 and MTHFR in relation to anterior encephalocele susceptibility in Northeast India. Birth Defects Res. 2017;109(6):432-44.
27. Etheredge AJ, Finnell RH, Carmichael SL, Lammer EJ, Zhu H, Mitchell LE et al. Maternal and infant gene-folate interactions and the risk of neural tube defects. Am J Med Genet A. 2012;158A(10):2439-46.
28. Boyles AL, Billups AV, Deak KL, Siegel DG, Mehltretter L, Slifer SH et al. Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions. Environ Health Perspect. 2006;114(10):1547-52.