Nurşen KESER, Ayfer PAZARBAŞI, Lütfiye ÖZPAK

Türk populasyonunda maternal MTHFR geni polimorfizmleri ve Down sendromlu çocuk sahibi olma riski

maç: Bu çalışmada Down sendromlu çocuk sahibi olan hastalarda MTHFR (Metilentetrahidrofolat redüktaz) geni C677T ve A1298C polimorfizmleri allel frekansları ve genotip dağılımlarını belirlemek ve bu genotipler ile folat ve homosistein düzeyleri arasındaki ilişkiyi araştırmak amaçlanmıştır.Gereç ve Yöntem: MTHFR geninin iki yaygın varyantı C677T ve A1298C, Türkiye Çukurova Bölgesi’ nde Down Sendromu tanısı almış çocukların annelerinde (hasta grubu, n=67) ve sağlıklı çocuk sahibi annelerde (kontrol grubu, n=66) araştırılmıştır. MTHFR genotipleri PZR amplifiye ürünlerinin RFLP analizi ile belirlenmiştir. Bulgular: C677T polimorfizmi için genotip ve allel frekansları bakımından hasta ve kontrol grupları arasındaki fark istatistiksel olarak anlamlı bulunmuştur. Hasta grubunda T alleli frekansına ait oran (%53.7) yüksek iken kontrol grubunda C alleli frekansına ait oran (%62.9) yüksektir. Ayrıca A1298C polimorfizmi için genotip ve allel frekansları bakımından hasta ve kontrol grupları arasındaki fark istatistiksel olarak anlamlı değildir. Hasta grubunda C alleli frekansına ait oran (%40.8) yüksek iken kontrol grubunda A alleli frekansına ait oran (%70.3) yüksektir. Sonuç: C677T polimorfizmi Down sendromlu çocuk sahibi olma durumu ile ilişkili iken A1298C polimorfizmi ilişkili değildir. 1298C alleli ile 677T alleli Down sendromu riski ile yakın ilişkili olabilir.

Anahtar Kelimeler:

Down sendromu, folik asit, homosistein, MTHFR, polimorfizm

Maternal polymorphisms of MTHFR gene and risk of Down syndrome offspring in Turkish population

Purpose: The aim of this study was to determine the allele frequencies and genotype distributions of MTHFR (methylenetetrahydrofolate reductase) gene C677T and A1298C polymorphisms and investigate the relationship between these genotypes and folate and homocysteine levels for mothers that having children with down syndrome. Materials and Methods: Two common variants C677T and A1298C of the MTHFR gene were screened in mothers with down syndrome children (n=67) and control mothers with healthy children (n=66) from Çukurova region of Turkey. The MTHFR genotypes were studied by RFLP analysis of PCR-amplified products. Results: The difference between case and control groups was found to be statistically significant in terms of genotype and allele frequencies for C677T polymorphism. While the rate of T allele frequency (%53.7) was detected great in case group, the rate of C allele frequency (%62.9) was determined great in control group. On the other hand, the difference between case and control groups wasn’t found to be statistically significant in terms of genotype and allele frequencies for A1298C polymorphism. While the rate of C allele frequency (%40.8) was detected great in case group, the rate of A allele frequency (%70.3) was determined great in control group. Conclusion: While C677T polymorphism is significantly associated with risk of having Down syndrome pregnancy, the A1298C polymorphism is not associated. The 1298C allele and 677T allele may be closely related to the risk of developing the having children with Down syndrome.

Keywords:

Down syndrome, folic acid, homocysteine, MTHFR, polymorphism,

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1. Dey S. Genetics and Etiology of Down Syndrome, Croatia, Intech, 2011.
2. Lejeune J, Gauthier M, Turpin R. Les chromosomes humains en culture de tissues. C R Acad Sci Gen. 1959;248:602-3.
3. Antonarakis SE. Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms Down Syndrome Collaborative Group. N Engl J Med. 1991;324:872-6.
4. Freeman SB, Allen EG, Oxford-Wright CL, Tinker SW, Druschel C, Hobbs CA et al. The National Down Syndrome Project: design and implementation. Public Health Rep. 2007;122:62-72.
5. Antonarakis SE, Petersen MB, McInnis MG, Adelsberger PA, Schinzel AA, Binkert F et al. The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms. Am J Hum Genet. 1992;50:544-50.
6. Yoon PW, Freeman SB, Sherman SL, Taft LF, Gu Y, Pettay D et al. Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of chromosomal error: a population-based study. Am J Hum Genet. 1996;58:628-33.
7. Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, Hine RJ et al. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet. 2000;67:623-30.
8. Christensen B, Rosenblatt DS. Effects of folate deficiency on embryonic development. Baillieres Clin Haematol. 1995;8:617-37.
9. Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a huge review. Am J Epidemiol. 2000;151:862-77.
10. Esfahani ST, Cogger EA, Caudill MA. Heterogeneity in the prevalence of methylenetetrahydrofolate reductase gene polymorphisms in women of different ethnic groups. J Am Diet Assoc. 2003;103:200-7.
11. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Acids Res. 1988;16:1215.
12. İzmi̇rli̇ M, Alpteki̇n D, Topçuoğlu MŞ, Güzel Aİ. Investigation of methylene tetrahydrofolate reductase gene polymorphisms in coronary by-passed patients due to coronary atherosclerosis etiology. Türkiye Klinikleri Cardiovascular Sciences. 2009;21:303-8.
13. Pozzi E, Vergani P, Dalpra L, Combi R, Silvestri D, Crosti F et al. Maternal polymorphisms for methyltetrahydrofolate reductase and methionine synthetase reductase and risk of children with Down syndrome. Am J Obstet Gynecol. 2009;200:636.e1-636.e6.
14. Muthuswamy S, Agarwal S. Do the MTHFR gene polymorphism and Down syndrome pregnancy association stands true? a case–control study of Indian population and meta-analysis. The Egyptian Journal of Medical Human Genetics. 2016;17:87-97.
15. Boduroğlu K, Alanay Y, Koldan B, Tuncbilek E. Methylenetetrahydrofolate reductase enzyme polymorphisms as maternal risk for Down Syndrome among turkish women. Am J Med Genet. 2004;127A:5-10.
16. Wu X, Wang X, Chan Y, Jia S, luo Y, Tang W. Folate m aetabolism gene polymorphisms MTHFR C677T and A1298C and risk for Down syndrome Offspring: a meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2013;167:154-9.
17. Uğuz N, Erden G, Güngör O, Bal C, Yıldırımkaya M. MTHFR Geninde c677t ve/veya a1298c polimorfizmi tespit edilen bireylerde bu polimorfizm sıklıklarının incelemesi. Journal of Clinical and Experimental Investigations. 2012;3:472-6.
18. Kohli U, Arora S, Kabra M, Ramakrishnan L, Gulati S, Pandey RM. Prevalence of MTHFR C677T polymorphism in north indian mothers having babies with trisomy 21 Down syndrome. Downs Syndr Res Pract. 2008;12:133-7.
19. James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, Gibson JB et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am J Clin Nutr. 1999;70:495-501.
20. Sheth JG, Sheth FJ. Gene polymorphism and folate metabolism: a maternal risk factor for Down syndrome. Indian Pediatr. 2003;40:115-23.
21. İzci Ay O, Ay ME, Erdal ME, Cayan F, Tekin S, Soylemez F et al. Folate metabolism gene polymorphisms and risk for Down syndrome offspring in turkish women. Genet Test Mol Biomarkers. 2015;19:191-7.
22. Herrera LA, Prada D, Andonegui MA, Dueñas-González. The epigenetic origin of aneuploidy. Curr Genomics. 2008;9:43-50.