MTHFR (methylenetetrahydrofolate reductase: EC SNPs (single-nucleotide polymorphisms) and homocysteine in patients referred for investigation of fertility

J Assist Reprod Genet. 2021 Sep;38(9):2383-2389. doi: 10.1007/s10815-021-02200-6. Epub 2021 Apr 29.


Purpose: MTHFR, one of the major enzymes in the folate cycle, is known to acquire single-nucleotide polymorphisms that significantly reduce its activity, resulting in an increase in circulating homocysteine. Methylation processes are of crucial importance in gametogenesis, involved in the regulation of imprinting and epigenetic tags on DNA and histones. We have retrospectively assessed the prevalence of MTHFR SNPs in a population consulting for infertility according to gender and studied the impact of the mutations on circulating homocysteine levels.

Methods: More than 2900 patients having suffered at least two miscarriages (2 to 9) or two failed IVF/ICSI (2 to 10) attempts were included for analysis of MTHFR SNPs C677T and A1298C. Serum homocysteine levels were measured simultaneously.

Results: We observed no difference in the prevalence of different genetic backgrounds between men and women; only 15% of the patients were found to be wild type. More than 40% of the patients are either homozygous for one SNP or compound heterozygous carriers. As expected, the C677T SNP shows the greatest adverse effect on homocysteine accumulation. The impact of MTHFR SNPs on circulating homocysteine is different in men than in women.

Conclusions: Determination of MTHFR SNPs in both men and women must be seriously advocated in the presence of long-standing infertility; male gametes, from MTHFR SNPs carriers, are not exempted from exerting a hazardous impact on fertility. Patients should be informed of the pleiotropic medical implications of these SNPs for their own health, as well as for the health of future children.

Keywords: DNA methylation; Fertility; Gametes; Gender prevalence; Homocysteine; MTHFR SNPs; Recurrent miscarriages.

MeSH terms

  • Abortion, Spontaneous / blood
  • Abortion, Spontaneous / epidemiology*
  • Abortion, Spontaneous / genetics
  • Female
  • France / epidemiology
  • Genetic Predisposition to Disease*
  • Genotype
  • Heterozygote
  • Homocysteine / blood*
  • Homozygote
  • Humans
  • Infertility / blood
  • Infertility / diagnosis*
  • Infertility / genetics
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Polymorphism, Single Nucleotide*
  • Retrospective Studies


  • Homocysteine
  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)