Relationship between genetic polymorphisms of methylenetetrahydrofolate reductase (C677T, A1298C, and G1793A) as risk factors for idiopathic male infertility

Reprod Sci. 2011 Mar;18(3):304-15. doi: 10.1177/1933719110385135. Epub 2010 Oct 26.


Objective: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

MeSH terms

  • Case-Control Studies
  • DNA / chemistry
  • DNA / genetics
  • Folic Acid / blood
  • Genotype
  • Homocysteine / blood
  • Humans
  • Infertility, Male / blood
  • Infertility, Male / enzymology*
  • Infertility, Male / genetics*
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide
  • Semen / physiology


  • Homocysteine
  • DNA
  • Folic Acid
  • Methylenetetrahydrofolate Reductase (NADPH2)