J Korean Med Sci.  2017 Dec;32(12):2029-2034. 10.3346/jkms.2017.32.12.2029.

Methylenetetrahydrofolate Reductase Polymorphisms and Risk of Recurrent Pregnancy Loss: a Case-Control Study

• Hwang KR
• Choi YM
• Kim JJ
• Lee SK
• Yang KM
• Paik EC
• Jeong HJ
• Jun JK
• Yoon SH
• Hong MA

• KMID: 2396382
• DOI: http://doi.org/10.3346/jkms.2017.32.12.2029

Abstract

The balance between coagulation and fibrinolysis is an essential part in early pregnancy. Mutations in methylenetetrahydrofolate reductase (MTHFR) gene lead to decreased activity of the enzyme and hyperhomocysteinemia, which then induces platelet aggregation by promoting endothelial oxidative damage, possibly resulting in adverse effect on maintenance of pregnancy. We investigated the role of MTHFR single nucleotide polymorphisms (SNPs), C677T and A1298C, in Korean patients with recurrent pregnancy loss (RPL). We conducted a prospective case-control study in the Korean population. Subjects included 302 women with 2 or more consecutive, unexplained, spontaneous miscarriages before 20 weeks of gestation and 315 control women without a history of recurrent miscarriages. The genotyping for C677T and A1298C polymorphisms was performed using the TaqMan assay. Continuous variables were compared using Student's t-test, and χ² test was used to evaluate differences in the genotype distributions between the RPL and the controls. The genotype distribution of both polymorphisms in the RPL group did not differ from those of the controls. For further analysis, if RPL patients were divided according to the numbers of pregnancy losses (≥ 2 and ≥ 3) neither group was significantly different compared with controls. MTHFR gene C677T and A1298C polymorphisms are not associated with idiopathic RPL in Korean women, suggesting that those may not be susceptible allelic variants or be deficient to cause RPL.

Keyword

MTHFR Gene; Recurrent Pregnancy Loss; Single-Nucleotide Polymorphisms; Korean

MeSH Terms

Abortion, Habitual
Abortion, Spontaneous
Case-Control Studies*
Female
Fibrinolysis
Genotype
Humans
Hyperhomocysteinemia
Methylenetetrahydrofolate Reductase (NADPH2)*
Platelet Aggregation
Polymorphism, Single Nucleotide
Pregnancy*
Prospective Studies
Methylenetetrahydrofolate Reductase (NADPH2)

Reference

1. Practice Committee of American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril. 2013; 99:63.

2. Coulam CB, Clark DA, Beer AE, Kutteh WH, Silver R, Kwak J, Stephenson M. Current clinical options for diagnosis and treatment of recurrent spontaneous abortion. Clinical guidelines recommendation Committee for Diagnosis and Treatment of Recurrent Spontaneous Abortion. Am J Reprod Immunol. 1997; 38:57–74.

3. Park CW, Han AR, Kwak-Kim J, Park SY, Han JY, Koong MK, Song IO, Yang KM. The role of methylenetetrahydrofolate reductase C677T polymorphism on the peripheral blood natural killer cell proportion in women with unexplained recurrent miscarriages. Clin Exp Reprod Med. 2011; 38:168–173.

4. Carp H, Salomon O, Seidman D, Dardik R, Rosenberg N, Inbal A. Prevalence of genetic markers for thrombophilia in recurrent pregnancy loss. Hum Reprod. 2002; 17:1633–1637.

5. Tranquilli AL, Saccucci F, Giannubilo SR, Cecati M, Nocchi L, Lorenzi S, Emanuelli M. Unexplained fetal loss: the fetal side of thrombophilia. Fertil Steril. 2010; 94:378–380.

6. Simcox LE, Ormesher L, Tower C, Greer IA. Thrombophilia and pregnancy complications. Int J Mol Sci. 2015; 16:28418–28428.

7. Farahmand K, Totonchi M, Hashemi M, Reyhani Sabet F, Kalantari H, Gourabi H, Mohseni Meybodi A. Thrombophilic genes alterations as risk factor for recurrent pregnancy loss. J Matern Fetal Neonatal Med. 2016; 29:1269–1273.

8. Forges T, Monnier-Barbarino P, Alberto JM, Guéant-Rodriguez RM, Daval JL, Guéant JL. Impact of folate and homocysteine metabolism on human reproductive health. Hum Reprod Update. 2007; 13:225–238.

9. Mtiraoui N, Zammiti W, Ghazouani L, Braham NJ, Saidi S, Finan RR, Almawi WY, Mahjoub T. Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and changes in homocysteine concentrations in women with idiopathic recurrent pregnancy losses. Reproduction. 2006; 131:395–401.

10. Trabetti E. Homocysteine, MTHFR gene polymorphisms, and cardio-cerebrovascular risk. J Appl Genet. 2008; 49:267–282.

11. Unfried G, Griesmacher A, Weismüller W, Nagele F, Huber JC, Tempfer CB. The C677T polymorphism of the methylenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage. Obstet Gynecol. 2002; 99:614–619.

12. Poursadegh Zonouzi A, Chaparzadeh N, Asghari Estiar M, Mehrzad Sadaghiani M, Farzadi L, Ghasemzadeh A, Sakhinia M, Sakhinia E. Methylenetetrahydrofolate reductase C677T and A1298C mutations in women with recurrent spontaneous abortions in the northwest of Iran. ISRN Obstet Gynecol. 2012; 2012:945486.

13. Kluijtmans LA, van den Heuvel LP, Boers GH, Frosst P, Stevens EM, van Oost BA, den Heijer M, Trijbels FJ, Rozen R, Blom HJ. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996; 58:35–41.

14. van der Put NM, Gabreëls F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998; 62:1044–1051.

15. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998; 64:169–172.

16. Goodman CS, Coulam CB, Jeyendran RS, Acosta VA, Roussev R. Which thrombophilic gene mutations are risk factors for recurrent pregnancy loss? Am J Reprod Immunol. 2006; 56:230–236.

17. Behjati R, Modarressi MH, Jeddi-Tehrani M, Dokoohaki P, Ghasemi J, Zarnani AH, Aarabi M, Memariani T, Ghaffari M, Akhondi MA. Thrombophilic mutations in Iranian patients with infertility and recurrent spontaneous abortion. Ann Hematol. 2006; 85:268–271.

18. Yenicesu GI, Cetin M, Ozdemir O, Cetin A, Ozen F, Yenicesu C, Yildiz C, Kocak N. A prospective case-control study analyzes 12 thrombophilic gene mutations in Turkish couples with recurrent pregnancy loss. Am J Reprod Immunol. 2010; 63:126–136.

19. Jeddi-Tehrani M, Torabi R, Zarnani AH, Mohammadzadeh A, Arefi S, Zeraati H, Akhondi MM, Chamani-Tabriz L, Idali F, Emami S, et al. Analysis of plasminogen activator inhibitor-1, integrin beta3, beta fibrinogen, and methylenetetrahydrofolate reductase polymorphisms in Iranian women with recurrent pregnancy loss. Am J Reprod Immunol. 2011; 66:149–156.

20. Nair RR, Khanna A, Singh K. MTHFR C677T polymorphism and recurrent early pregnancy loss risk in north Indian population. Reprod Sci. 2012; 19:210–215.

21. Luo L, Chen Y, Wang L, Zhuo G, Qiu C, Tu Q, Mei J, Zhang W, Qian X, Wang X. Polymorphisms of genes involved in the folate metabolic pathway impact the occurrence of unexplained recurrent pregnancy loss. Reprod Sci. 2015; 22:845–851.

22. Kobashi G, Kato EH, Morikawa M, Shimada S, Ohta K, Fujimoto S, Minakami H, Yamada H. MTHFR C677T Polymorphism and factor V Leiden mutation are not associated with recurrent spontaneous abortion of unexplained etiology in Japanese women. Semin Thromb Hemost. 2005; 31:266–271.

23. Coulam CB, Jeyendran RS, Fishel LA, Roussev R. Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage. Am J Reprod Immunol. 2006; 55:360–368.

24. Vettriselvi V, Vijayalakshmi K, Paul SF, Venkatachalam P. ACE and MTHFR gene polymorphisms in unexplained recurrent pregnancy loss. J Obstet Gynaecol Res. 2008; 34:301–306.

25. Bae J, Choi DH, Kang MS, Cha SH, Oh D, Kim NK. Effect of methylenetetrahydrofolate reductase and thymidylate synthase enhancer region polymorphisms on the risk of idiopathic recurrent spontaneous abortion in a Korean population. Fertil Steril. 2009; 91:1560–1562.

26. Settin A, Elshazli R, Salama A, ElBaz R. Methylenetetrahydrofolate reductase gene polymorphisms in Egyptian women with unexplained recurrent pregnancy loss. Genet Test Mol Biomarkers. 2011; 15:887–892.

27. Yousefian E, Kardi MT, Allahveisi A. Methylenetetrahydrofolate reductase C677T and A1298C polymorphism in Iranian women with idiopathic recurrent pregnancy losses. Iran Red Crescent Med J. 2014; 16:e16763.

28. Kim JJ, Choi YM, Lee SK, Yang KM, Paik EC, Jeong HJ, Jun JK, Han AR, Hong MA. The PAI-1 4G/5G and ACE I/D polymorphisms and risk of recurrent pregnancy loss: a case-control study. Am J Reprod Immunol. 2014; 72:571–576.

29. Wiwanitkit V. Roles of methylenetetrahydrofolate reductase C677T polymorphism in repeated pregnancy loss. Clin Appl Thromb Hemost. 2005; 11:343–345.

30. Ren A, Wang J. Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis. Fertil Steril. 2006; 86:1716–1722.

31. Wu X, Zhao L, Zhu H, He D, Tang W, Luo Y. Association between the MTHFR C677T polymorphism and recurrent pregnancy loss: a meta-analysis. Genet Test Mol Biomarkers. 2012; 16:806–811.

32. Cao Y, Xu J, Zhang Z, Huang X, Zhang A, Wang J, Zheng Q, Fu L, Du J. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a meta-analysis. Gene. 2013; 514:105–111.

33. Nair RR, Khanna A, Singh R, Singh K. Association of maternal and fetal MTHFR A1298C polymorphism with the risk of pregnancy loss: a study of an Indian population and a meta-analysis. Fertil Steril. 2013; 99:1311–1318.e4.

34. Rai V. Methylenetetrahydrofolate reductase gene A1298C polymorphism and susceptibility to recurrent pregnancy loss: a meta-analysis. Cell Mol Biol (Noisy-le-grand). 2014; 60:27–34.

35. Yang Y, Luo Y, Yuan J, Tang Y, Xiong L, Xu M, Rao X, Liu H. Association between maternal, fetal and paternal MTHFR gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss: a comprehensive evaluation. Arch Gynecol Obstet. 2016; 293:1197–1211.

36. Chen H, Yang X, Lu M. Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and meta-analysis. Arch Gynecol Obstet. 2016; 293:283–290.

37. Rai V. Methylenetetrahydrofolate reductase C677T polymorphism and recurrent pregnancy loss risk in Asian population: a meta-analysis. Indian J Clin Biochem. 2016; 31:402–413.

38. Sull JW, Jee SH, Yi S, Lee JE, Park JS, Kim S, Ohrr H. The effect of methylenetetrahydrofolate reductase polymorphism C677T on cervical cancer in Korean women. Gynecol Oncol. 2004; 95:557–563.

39. Kang S, Kim JW, Kang GH, Park NH, Song YS, Kang SB, Lee HP. Polymorphism in folate- and methionine-metabolizing enzyme and aberrant CpG island hypermethylation in uterine cervical cancer. Gynecol Oncol. 2005; 96:173–180.

40. Tong SY, Kim MK, Lee JK, Lee JM, Choi SW, Friso S, Song ES, Lee KB, Lee JP. Common polymorphisms in methylenetetrahydrofolate reductase gene are associated with risks of cervical intraepithelial neoplasia and cervical cancer in women with low serum folate and vitamin B12. Cancer Causes Control. 2011; 22:63–72.