Relationship Between Genetic Polymorphisms of Methylenetetra hydrofolate Reductase (C677T, A1298C, and G1793A) as Risk Factors for Idiopathic Male Infertility



The human methylenetetrahydrofolate reductase (MTHFR) gene plays a crucial role in folate metabolism. Data regarding the influence of MTHFR gene polymorphisms on male fertility status are scarce and conflicting. We determined associations between 3 MTHFR gene polymorphisms (C677T, A1298C, and G1793A), serum folate, and total homocysteine (tHcy) levels, with male fertility status and semen parameters.


MTHFR genotypes were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique and serum tHcy, folate, and vitamin B12 concentrations were measured in 164 men with idiopathic infertility and 328 healthy participants.


There was a significant difference in genotype frequency distribution of MTHFR C677T polymorphism between infertile patients and controls (P =.004). The 677T allele carriers (TC or TT) had a significantly increased risk of infertility compared with the CC homozygotes (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.21-2.75, and OR = 2.68, 95% CI = 1.84-3.44, respectively), in a logistic regression model after adjustment for confounding factors. Men with the 677T, 1298C, and 1793G alleles showed significantly higher serum tHcy and lower folate levels (all Ps <.01). We found a positive correlation between serum folate concentrations and sperm density (r =.74, P =.001), percentage of sperm with progressive motility (r =.68, P =.001), as well as percentage of sperm with normal morphology (r =.72, P =.001).


MTHFR C677T polymorphism is associated with an increased risk of idiopathic male infertility. Further study on the biologic role that this polymorphism plays in the development of infertility may lead to better understanding of the etiology of impaired spermatogenesis.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 510

This is the net price. Taxes to be calculated in checkout.


  1. 1.

    Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111–113.

  2. 2.

    Goyette P, Pai A, Milos R, et al. Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome. 1998;9(8):652–656.

  3. 3.

    Goyette P, Sumner JS, Milos R, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet. 1994;7(2):195–200.

  4. 4.

    Nuti F, Krausz C. Gene polymorphisms/mutations relevant to abnormal spermatogenesis. Reprod Biomed Online. 2008;16(4):504–513.

  5. 5.

    Jacques PF, Bostom AG, Williams RR, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93(1):7–9.

  6. 6.

    Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost. 1997;78(1):523–526.

  7. 7.

    Rady PL, Szucs S, Grady J, et al. Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas: a report of a novel MTHFR polymorphic site, G1793A. Am J Med Genet. 2002;107(2):162–168.

  8. 8.

    Matthews RG. Methylenetetrahydrofolate reductase: a common human polymorphism and its biochemical implications. Chem Rec. 2002;2(1):4–12.

  9. 9.

    Guéant-Rodriguez RM, Juilliére Y, Candito M, et al. Association of MTRRA66G polymorphism (but not of MTHFR C677T and A1298C, MTRA2756G, TCN C776G) with homocysteine and coronary artery disease in the French population. Thromb Haemost. 2005;94(3):510–515.

  10. 10.

    Rayburn WF, Stanley JR, Garrett ME. Periconceptional folate intake and neural tube defects. J Am Coll Nutr. 1996;15(2):121–125.

  11. 11.

    Swann AC, Geller B, Post RM, et al. Practical clues to early recognition of bipolar disorder: a primary care approach. Prim Care Companion J Clin Psychiatry. 2005;7(1):15–21.

  12. 12.

    Bailey LB. Folate, methyl-related nutrients, alcohol, and the MTHFR 677CYT polymorphism affect cancer risk: intake recommendations. J Nutr. 2003;133(11 suppl 1):3748S–3753S.

  13. 13.

    Dedoussis GV, Panagiotakos DB, Pitsavos C, et al. An association between the methylenetetrahydrofolate reductase (MTHFR) C677Tmutation and inflammation markers related to cardiovascular disease. Int J Cardiol. 2005;100(3):409–414.

  14. 14.

    Smulders YM, Smith DE, Kok RM, et al. Red blood cell folate vitamer distribution in healthy subjects is determined by the methylenetetrahydrofolate reductase C677T polymorphism and by the total folate status. J Nutr Biochem. 2007;18(10):693–699.

  15. 15.

    Doshi SN, McDowell IF, Moat SJ, et al. Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation. 2002;105(1):22–26.

  16. 16.

    Boxmeer JC, Smit M, Utomo E, et al. Low folate in seminal plasma is associated with increased sperm DNA damage. Fertil Steril. 2009;92(2):548–556.

  17. 17.

    Wallock LM, Tamura T, Mayr CA, Johnston KE, Ames BN, Jacob RA. Low seminal plasma folate concentrations are associated with low sperm density and count in male smokers and nonsmokers. Fertil Steril. 2001;75(2):252–259.

  18. 18.

    Koury MJ, Horne DW, Brown ZA, et al. Apoptosis of late-stage erythroblasts in megaloblastic anemia: association with DNA damage and macrocyte production. Blood. 1997;89(12):4617–4623.

  19. 19.

    Ganji V, Kafai MR. Frequent consumption of milk, yogurt, cold breakfast cereals, peppers, and cruciferous vegetables and intakes of dietary folate and riboflavin but not vitamins B-12 and B-6 are inversely associated with serum total homocysteine concentrations in the US population. Am J Clin Nutr. 2004;80(6):1500–1507.

  20. 20.

    Friso S, Choi SW. Gene-nutrient interactions in one-carbon metabolism. Curr Drug Metab. 2005;6(1):37–46.

  21. 21.

    Ebisch IM, Peters WH, Thomas CM, Wetzels AM, Peer PG, Steegers-Theunissen RP. Homocysteine, glutathione and related thiols affect fertility parameters in the (sub)fertile couple. Hum Reprod. 2006;21(7):1725–1733.

  22. 22.

    Park JH, Lee HC, Jeong YM, et al. MTHFR C677 T polymorphism associates with unexplained infertile male factors. J Assist Reprod Genet. 2005;22:361–368.

  23. 23.

    Singh K, Singh SK, Sah R, Singh I, Raman R. Mutation C677 T in the methylenetetrahydrofolate reductase gene is associated with male infertility in an Indian population. Int J Androl. 2005;28(2):115–119.

  24. 24.

    Ferlin A, Raicu F, Gatta V, Zuccarello D, Palka G, Foresta C. Male infertility: role of genetic background. Reprod Biomed Online. 2007;14(6):734–745.

  25. 25.

    World Health Organization.WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. 4th ed. Cambridge, UK: Cambridge University Press; 1999.

  26. 26.

    Safarinejad MR, Shafiei N, Safarinejad S. Relationship between three polymorphisms of methylenetetrahydrofolate reductase (MTHFR C677T, A1298C, and G1793A) gene and risk of prostate cancer: a case-control study. Prostate. 2010 Jun 16. [Epub ahead of print].

  27. 27.

    van der Put NM, Gabreels F, Stevens EM, 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):1044–1051.

  28. 28.

    Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001;68(4):978–89.

  29. 29.

    Chen J, Ma J, Stampfer MJ, Palomeque C, Selhub J, Hunter DJ. Linkage disequilibrium between the 677C>T and 1298A>C polymorphisms in human methylenetetrahydrofolate reductase gene and their contributions to risk of colorectal cancer. Pharmacogenetics. 2002;12(4):339–342.

  30. 30.

    Stevenson RE, Schwartz CE, Du YZ, Adams MJ Jr. Differences in methylenetetrahydrofolate reductase genotype frequencies, between Whites and Blacks. Am J Hum Genet. 1997;60(1):229–230.

  31. 31.

    Schneider JA, Rees DC, Liu YT, Clegg JB. Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet. 1998;62(5):1258–1260.

  32. 32.

    Blount BC, Mack MM, Wehr CM, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A. 1997;94(7):3290–3295.

  33. 33.

    Friso S, Choi SW, Girelli D, et al. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci U S A. 2002;99(8):5606–5611.

  34. 34.

    Papoutsakis C, Yiannakouris N, Manios Y, et al. Plasma homocysteine concentrations in Greek children are influenced by an interaction between the methylenetetrahydrofolate reductase C677T genotype and folate status. J Nutr. 2005;135(3):383–388.

  35. 35.

    Bezold G, Lange M, Peter RU. Homozygous methylenetetrahydrofolate reductase C677T mutation and male infertility. N Engl J Med. 2001;344(15):1172–1173.

  36. 36.

    ZC A, Yang Y, Zhang SZ, Li N, Zhang W. Single nucleotide polymorphism C677T in the methylenetetrahydrofolate reductase gene might be a genetic risk factor for infertility for Chinese men with azoospermia or severe oligozoospermia. Asian J Androl. 2007;9(1):57–62.

  37. 37.

    Ebisch IM, van Heerde WL, Thomas CM, van der Put N, Wong WY, Steegers-Theunissen RP. C677T methylenetetrahydrofolate reductase polymorphism interferes with the effects of folic acid and zinc sulfate on sperm concentration. Fertil Steril. 2003;80(5):1190–1194.

  38. 38.

    Stuppia L, Gatta V, Scarciolla O, et al. The methylenetethrahydrofolate reductase [MTHFR] C677T polymorphism and male infertility in Italy. J Endocrinol Invest. 2003;26(7):620–622.

  39. 39.

    Paracchini V, Garte S, Taioli E. MTHFR C677T polymorphism, GSTM1 deletion and male infertility: a possible suggestion of a gene-gene interaction?. Biomarkers. 2006;11(1):53–60.

  40. 40.

    Sheweita SA, Tilmisany AM, Al-Sawaf H. Mechanisms of male infertility: role of antioxidants. Curr Drug Metab. 2005;6(5):495–501.

  41. 41.

    Selhub JL, Miller JW. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transulfuration of homocysteine. Am J Clin Nutr. 1991;55(1):131–138.

  42. 42.

    Nygard O, Refsum H, Ueland PM, Vollset SE. Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study. Am J Clin Nutr. 1998;67(2):263–270.

Download references

Author information

Correspondence to Mohammad Reza Safarinejad MD.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Safarinejad, M.R., Shafiei, N. & Safarinejad, S. Relationship Between Genetic Polymorphisms of Methylenetetra hydrofolate Reductase (C677T, A1298C, and G1793A) as Risk Factors for Idiopathic Male Infertility. Reprod. Sci. 18, 304–315 (2011).

Download citation


  • infertility
  • male factor
  • gene
  • polymorphism