Methylation is a crucially important ubiquitous biochemical process, which covalently adds methyl groups to a variety of molecular targets. It is the key regulatory process that determines the acquisition of imprinting and epigenetic marks during gametogenesis. Methylation processes are dependent upon two metabolic cycles, the folates and the one-carbon cycles. The activity of these two cycles is compromised by single nucleotide polymorphisms (SNPs) in the gene encoding the Methylenetetrahydrofolate reductase (MTHFR) enzyme. These SNPs affect spermatogenesis and oocyte maturation, creating cytologic/chromosomal anomalies. The two main MTHFR SNP variants C677T (c.6777C>T) and A1298C (c.1298A>C) together with serum homocysteine levels were tested in men with >3 years’ duration of infertility who had failed several ART attempts with the same partner. These patients are often classified as having “idiopathic infertility”. We observed that the genetic status with highest prevalence in this group is the heterozygous C677T, followed by the combined heterozygous C677T/A1298C, and then A1298C; these three variants represent 65% of our population. Only 13.1% of the patients tested are wild type (WT), C677C/A1298A). The homozygous 677TT and the combined heterozygote 677CT/1298AC groups have the highest percentage of patients with an elevated circulating homocysteine level of >15 µMolar (57.8% and 18.8%, respectively, which is highly significant for both). Elevated homocysteine is known to be detrimental to spermatogenesis, and the population with this parameter is not marginal. In conclusion, determination of these two SNPs and serum homocysteine should not be overlooked for patients with severe infertility of long duration, including those with repeated miscarriages. Patients must also be informed about pleiotropic medical implications relevant to their own health, as well as to the health of future children.
Keywords: A1298C; C677T; Caucasian men population; MTHFR SNP; homocysteine; hypofertility.