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

Yves Ménézo,Brian Dale,Jean Clement Sage,Edouard Servy,Edouard Amar,P Marès ,C Brami ,Paul Neveux,Laetitia Jacquesson-Fournols,Arthur Clément ,Guiseppe D' Amato ,To Minh Huong,J Chouteau ,Silvia Álvarez ,D Cornet ,Patrice Clément ,Marc Cohen,Pasquale Patrizio,Michel Brack,Géraldine Viot

doi:10.1007/s10815-021-02200-6

Abstract

PurposeMTHFR, 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.MethodsMore 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.ResultsWe 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.ConclusionsDetermination 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.

Highlights

It is generally accepted that human fertility is on a decreasing trajectory, with an increasing time to reach pregnancy (TPP) [1, 2] that is not related to couples’ intent
Determination of methylene tetrahydrofolate reductase (MTHFR) SNPs in both men and women must be seriously advocated in the presence of longstanding infertility; male gametes, from MTHFR SNPs carriers, are not exempted from exerting a hazardous impact on fertility
Homocysteine is toxic to cells, as it competes with methionine for the same transporter and inhibits methylation [4]: it must be regenerated to methionine via the one-carbon cycle (1-CC), supported by the folate cycle

Summary

Results

Serum Hcy levels between 3.5 and 110.6 μmoles/L were observed in our overall population. In the total population of 2614 patients tested for Hcy, 1219 patients were found to have Hcy > 10 μmoles/L (46.6% of the patients); 72.8% of the men and 23.5% of the women are included in this range (Fig. 3). 17.2 % and only 3.4% of the women had levels over the critical value of 15 μmoles/L (259 patients, 9.9% of the whole population). Thirty one patients had a Hcy >30 μmoles/L (twice the critical value of 15 μmoles/L) 30 men (twenty seven 677TT, one 677CT and two 677CT/1298AC) and one woman (Hcy = 97.3 μmoles/ L) carrying no MTHFR mutation. Homocysteinemia > 15 μmoles/L and genetic status in the overall population (Fig. 4). A large majority (more than 2/3) of the elevated homocysteinemia levels were found in individuals carrying the 677CT isoform: 42.6%

Conclusions

Introduction

Materials and methods

Methyl THF

Discussion and conclusions