Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and male infertility risk

He, Xiaofeng; Ye, Xianghua

doi:10.1097/md.0000000000023662

Cited by 7 publications

(4 citation statements)

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“…Publications mention that MTHFR gene variants are associated with non-obstructive azoospermia (Li et al 2015). Also, scienti c studies describe the association of MTHFR gene variants with azoospermia and oligoasthenoteratospermia -a clinically signi cant NM_005957.5(MTHFR):c.[677C > T];[677=] variant was identi ed in this gene (Han et al 2020). Variants in the DCC gene are found in cases of Kallman syndrome, which is also associated with male infertility (Bouilly et al 2027).…”

Section: Discussionmentioning

confidence: 99%

Analysis of partial Y chromosome microdeletions and NGS data in Lithuanian infertile men

Čižaitė,

Žukauskaitė,

Tumienė

2024

Preprint

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Infertility is a complex pathological condition that affects the male population worldwide. Male infertility is often caused by changes in the morphology and number of spermatozoa. Many of infertility cases remain unexplained, genetic causes are being discovered, including changes in chromosomes and single genes. While Y chromosome microdeletions are the most common cause of spermatogenesis disorders, failure to identify them leads to the search for new candidate genes, de novo pathogenic genomic variants associated with male infertility using next generation sequencing. The aim of this study is to investigate genetic profile of infertile men in the Lithuanian population using candidate gene approach as well as to evaluate the significance of partial Y chromosome microdeletions. The obtained results showed that the detected partial Y chromosome (sY121, sY1192, sY153 and sY1191 markers) microdeletions in the azoospermia factor region do not explain infertility cases and require more research. After candidate-gene next generation sequencing analysis in the cohort of 18 infertile men from Lithuania, genome variants in genes DPY19L2, DCC, and MTHFR were identified for three (17%) individuals, confirming the infertility phenotype. In five (28%) of individuals variants of uncertain clinical significance were identified in BRCA1, BRCA2, PKD1, CSMD1, SBF1, DNAH8, and TP63 genes, which are potentially associated with male infertility. This confirms that the next generation method based on the supplemented gene candidate list is useful for the identification of genetic causes of male infertility.

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Section: Discussionmentioning

confidence: 99%

Analysis of partial Y chromosome microdeletions and NGS data in Lithuanian infertile men

Čižaitė,

Žukauskaitė,

Tumienė

2024

Preprint

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“…However, these are not benign and are a source of several pathologies [ 34 , 35 , 36 ]. They do affect fertility [ 13 , 14 , 15 , 16 , 17 , 19 , 21 , 28 , 37 ]. These isoforms are highly prevalent in Mediterranean and Latino populations and in Chinese Han and Zhuang ethnicities, where it can reach 70% of the population.…”

Section: Discussionmentioning

confidence: 99%

“…The resulting folate deficiency jeopardizes DNA stability and methylation processes [ 11 ]. The trilogy MTHFR SNP, Hcy and folate deficiency have a major impact on male [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ] and female [ 21 , 22 , 23 , 24 , 25 ] gametogenesis, embryogenesis implantation/miscarriages [ 26 , 27 , 28 ], and even pregnancy complications “from gametes to infant delivery”. Associations between maternal, paternal, and then fetal MTHFR gene C677T and A1298C polymorphisms will affect DNA stability [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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

Clément¹,

Amar

Brami

et al. 2022

Biomolecules

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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.

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“…This is the most seen and observed SNP in the MTHFR gene [ 16 ]. During polymorphism of this gene, there is C-to-T movement at nucleotide 677 in exon 4 points where cytosine (C) is mutated to a thymine (T) at the coding region MTHFR gene in humans, resulting in an alanine-valine mutation where alanine position is replaced with valine residues (Ala222Val) consequently, generating a decrease in enzyme activity [ 17 ]. This leads to a phenotype high in homocysteine and readily deactivated by heat.…”

Section: Reviewmentioning

confidence: 99%

MTHFR Gene-Polymorphism and Infertile Men in Indian Population: A Systematic Literature Review

More¹,

Gajbe²,

Olatunji³

et al. 2022

Cureus

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Single nucleotide polymorphisms (SNPs) in the genetic makeup of the methylenetetrahydrofolate reductase gene (MTHFR C677-T, A1298-C, and G1793-A) alongside environmental and lifestyle component has shown some links as a potential factor responsible for male infertility across the globe posing huge genetic vulnerability to the gender. However, SNPs in the MTHFR gene implicated in male infertility are not without their own controversial results even within the same population. The goal of this study was to provide comprehensive insights into the controversial nature of MTHFR gene polymorphism on male infertility across all Indian populations as well as other ethnicities. The electronic PubMed database was utilized to conduct and select eligible studies for this systematic review (update to December 2021). Only high-quality studies with a link between MTHFR polymorphisms and male infertility were included based on our exclusion and inclusion criteria. The connection between the MTHFR gene polymorphism and male infertility in Indian population studies was evaluated using odds ratios (ORs) with a 95% confidence interval (CI). A total of five studies presenting 1,237 cases and 1,044 controls were assessed for this study. The collective results revealed that MTHFR C667-T and A1298-C gene polymorphism were significantly linked with an increased chance of male infertility both in south India and north India, however, with some conflicting results. Interestingly, no study has been carried out to investigate the impact of G1793-A polymorphism on infertile males in the Indian population at the time of our report. Results generated from the few case-control evaluated on MTHFR gene polymorphism in the Indian population are found to conflict with some extrinsic factors (such as nutritional status-folate metabolism, lifestyle, varying recruitment procedures, and epigenetic elements) identified to have played some critical roles. Therefore, broader studies across all regions in India addressing the grave impact of MTHFR gene polymorphism on male infertility are of utmost importance.

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Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and male infertility risk

Abstract: Supplemental Digital Content is available in the text

Cited by 7 publications

References 78 publications

Analysis of partial Y chromosome microdeletions and NGS data in Lithuanian infertile men

Analysis of partial Y chromosome microdeletions and NGS data in Lithuanian infertile men

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

MTHFR Gene-Polymorphism and Infertile Men in Indian Population: A Systematic Literature Review

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