MTHFR SNPs (Methyl Tetrahydrofolate Reductase, Single Nucleotide Polymorphisms) C677T and A1298C Prevalence and Serum Homocysteine Levels in >2100 Hypofertile Caucasian Male Patients

Abstract

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.

Homozygous C677T Methylenetetrahydrofolate Reductase (MTHFR) Polymorphism as a Risk Factor for Endometriosis: A Retrospective Case–Control Study

“…Aberrant DNA methylation has been reported in endometriotic tissue in genes implicated in the hormonal and inflammatory factors of endometriosis pathogenesis (estrogen and progesterone receptors ERα, Erβ, and Prβ, the aromatase CYP19, the homebox protein HOXA-10, and the cyclooxygenase COX-2) [7][8][9][10][11]14]. Moreover, there is preliminary evidence about the association between MTHFR polymorphisms, endometriosis, and endometriosis-related infertility [15][16][17]. Therefore, it is possible to hypothesize that MTHFR polymorphisms may act as one of the risk factors for endometriosis, supporting mechanisms of aberrant DNA methylation in critical genes of endometriosis pathogenesis.…”

“…Moreover, there is preliminary evidence about the association between MTHFR polymorphisms, endometriosis, and endometriosis-related infertility [15][16][17]. Therefore, it is possible to hypothesize that MTHFR polymorphisms may act as one of the risk factors for endometriosis, supporting mechanisms of aberrant DNA methylation in critical genes of endometriosis pathogenesis.…”

Hyperhomocysteinemia in hypofertile male patients can be alleviated by supplementation with 5MTHF associated with one carbon cycle support

“…Five major conclusions can be drawn. HHcy in hypofertile males is not “anecdotic” ( 8 , 27 ). Hcy is well-known to induce pathology, including cancers ( 29 ), cardiovascular disease ( 30 ), dementia ( 31 ), and with an impact on health in general ( 1 , 2 ).…”

“…The techniques have been previously described ( 27 , 28 ). Tests are carried out on 5 µl venous blood samples, using the LAMP human MTHFR mutation kit (LaCAR, MDx, Belgium; https://www.lacar-mdx.com/kit/thrombophilic-profile/mthfr-c677t ; https://www.lacar-mdx.com/kit/thrombophilic-profile/mthfr-a1298c ) based on selective hybridization.…”

Susceptibility to hypertension based on MTHFR rs1801133 single nucleotide polymorphism and MTHFR promoter methylation

“…A1298C (rs1801131) and C677T (rs1801133) are the major MTHFR variants that impair the gene’s activities ( 44 , 45 ). A1298C results from adenine (A) to cytosine (C) substitution at position 1,298 in exon 7 of MTHFR while C677T (rs1801133) results when thymidine (T) replaces cytosine (C) at position 677 ( 45 ).…”