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

MTHFR (methylenetetrahydrofolate reductase: EC 1.5.1.20) SNPs (single-nucleotide polymorphisms) and homocysteine in patients referred for investigation of fertility

Yves Ménézo  1   2 , Pasquale Patrizio  3 , Silvia Alvarez  4 , Edouard Amar  5 , Michel Brack  6 , Charles Brami  5 , Jacques Chouteau  7 , Arthur Clement  8 , Patrice Clement  8 , Marc Cohen  9 , Dominique Cornet  4 , Brian Dale  10   11 , Guiseppe D' Amato  12 , Laetitia Jacquesson-Fournols  4 , Pierre Mares  13 , Paul Neveux  14 , Jean Clement Sage  15 , Edouard Servy  16 , To Minh Huong  15 , Geraldine Viot  4
Affiliations

MTHFR (methylenetetrahydrofolate reductase: EC 1.5.1.20) SNPs (single-nucleotide polymorphisms) and homocysteine in patients referred for investigation of fertility

Yves Ménézo et al. J Assist Reprod Genet. 2021 Sep.

Abstract

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.

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Figures

Fig. 1
Fig. 1
Homocysteine (Hcy) generation. SAH (S-adenosyl homocysteine) is formed after target methylation with release of a methyl group via SAM (S-adenosyl methionine). Free Hcy is then released from SAH by SAH hydrolase
Fig. 2
Fig. 2
The one-carbon (1-CC) and folate cycles. A narrow gap at the level of MTHFR results in accumulation of unmetabolized folic acid, with feedback inhibition by excess substrate (Michelis and Menten law); the folate cycle may be reversed. A shortage of vitamin B12 (e.g., malabsorption) inactivates methionine synthase, with impairment of methionine synthase activity and accumulation of homocysteine. Mutations in the CBS pathway may also induces Hcy accumulation
Fig. 3
Fig. 3
Serum Hcy according to gender (M, men; W, women)
Fig. 4
Fig. 4
Patients having a blood Hcy > 15 μmoles/L according to the mutational status
See this image and copyright information in PMC

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