Association of the MTHFR C677T (rs1801133) polymorphism with idiopathic male infertility in a local Pakistani population

The present study determined an association between idiopathic sperm disorders in a local Pakistani infertile male population and the MTHFR C677T polymorphism. After ruling out non genetic factors, a total of 437 idiopathic infertile men including 57 azoospermic, 66 oligospermic, 44 asthenozoospermic, 29 teratozoospermic, 20 oligoasthenospermic and 221 infertile normospermic men were recruited. Furthermore, 218 normospermic fertile men, who had two children (or more) were included as controls. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to determine MTHFR C677T (rs1801133) polymorphism. A significant association of the minor MTHFR 677T allele with male infertility was observed (p <0.05). In addition, men with MTHFR 677 CT and TT genotypes were at a greater risk [odds ratio (OR): 1.81, 95% confidence interval (95% CI): 1.17-2.80, p = 0.008 and OR: 9.24, 95% CI: 1.20-70.92, p = 0.032, respectively] of infertility. All the subgroups of male infertility (azoospermic, oligospermic, asthenospermic, oligoasthenoteratospermic (OAT) and normospermic infertile) had significantly (p <0.05) higher frequencies of CT and TT genotypes when compared to fertile men. The combined genotypes (CT + TT) were also found significantly (OR: 2.01, 95% CI: 1.31-3.08, p <0.001) associated with male infertility. The results suggest that the polymorphism might be a factor of male infertility in the Pakistani population.

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and antipsychotic-induced metabolic disturbances in first-episode schizophrenia patients

IntroductionThere is a scarcity of prospective studies addressing the influence of the methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms on antipsychotic-induced metabolic changes in first-episode schizophrenia (FES) patients.ObjectivesWe aimed at investigating metabolic side effects of second-generation antipsychotics (SGAs) with respect to the MTHFR gene polymorphisms in FES patients.MethodsPolymorphisms in the MTHFR gene (C677T and A1298C) were investigated with respect to changes in body mass index (BMI) and waist circumference (WC) together with serum levels of glucose, lipids, homocysteine, vitamin B12 and folate after 12 weeks of treatment with SGAs in 135 FES patients.ResultsThe 677TT genotype was associated with significantly higher BMI, WC and serum levels of triglycerides, as well as significantly lower folate levels at baseline. Additionally, the 677T allele was associated with significantly lower folate levels at baseline. The 677CC homozygotes had significantly higher increase in BMI and serum levels of triglycerides. The 677TT genotype predicted significantly higher increase in homocysteine levels and significantly higher decrease in folate levels. These associations were also significant in the allelic analysis. Only the patients with the 677T allele had significantly lower folate levels and significantly higher homocysteine levels at the follow-up. The 677T allele was also related to significantly lower increase in WC. The 1298CC homozygotes had significantly higher weight gain in the course of treatment with SGAs.ConclusionsThe MTHFR gene polymorphisms might predict antipsychotic-induced weight gain in FES patients. In addition, the MTHFR C677T polymorphism might be also predictive with respect to other metabolic adversities of SGAs.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Association of C677T transition of the human methylenetetrahydrofolate reductase (MTHFR) gene with male infertility

The human methylenetetrahydrofolate reductase (MTHFR) gene encodes one of the key enzymes in folate metabolism. This gene is located on chromosome 1 (1p36.3), which has 12 exons. The aim of the present study was to investigate the possible association of the two (C677T and A1298C) polymorphisms of this gene with male infertility. In a case-control study, 250 blood samples were collected from IVF centres in Sari and Babol (Iran): 118 samples were from oligospermic men and 132 were from controls. Two single nucleotide polymorphisms of the MTHFR genotype were detected using polymerase chain reaction–restriction fragment length polymorphism. There was no association found between the A1298C variant and male infertility. However, carriers of the 677T allele (CT and TT genotypes) were at a higher risk of infertility than individuals with other genotypes (odds ratio 1.84; 95% confidence interval 1.11–3.04; P = 0.0174). Structural analysis of human MTHFR flavoprotein showed that C677T transition played an important role in the change in affinity of the MTHFR–Flavin adenine dinucleotide binding site. Based on our results, we suggest that C677T transition in MTHFR may increase the risk of male infertility, and detection of the C677T polymorphism biomarker may be helpful in the screening of idiopathic male infertility.

The influence of folate pathway polymorphisms on high-dose methotrexaterelated toxicity and survival in children with non-Hodgkin malignant lymphoma

Background. We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX) related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL). Patients and methods. In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms. Results. Carriers of at least one MTHFR 677T allele had significantly higher MTX area under the time-concentration curve levels at third MTX cycle (P = 0.003). These patients were also at higher odds of leucopoenia (P = 0.006) or thrombocytopenia (P = 0.041) and had higher number of different HD-MTX-related toxicity (P = 0.035) compared to patients with wild-type genotype. Conclusions. Our results suggest an important role of MTHFR 677C>T polymorphism in the development of HD-MTXrelated toxicity in children with NHL.

MTHFR C677T and A1298C Genotypes and Haplotypes in Slovenian Couples with Unexplained Infertility Problems and in Embryonic Tissues from Spontaneous Abortions

The objective of this study was to analyze the methylenetetrahydrofolate reductases (MTHFRs) C677T and A1298C genotype distributions in couples with unexplained fertility problems (UFP) and healthy controls, and to analyze the genotype and haplotype distribution in spontaneously aborted embryonic tissues (SAET) using allele specific polymerase chain reaction (PCR) in 200 probands with UFP, 353 samples of SAET and 222 healthy controls. The analysis revealed a significant overall representation of the 677T allele in male probands from couples with UFP (p = 0.036). The combined genotype distribution for both MTHFR polymorphisms was also significantly altered (χ2 21.73, p <0.001) although female probands made no contribution (c2 1.33, p = 0.72). The overall representation of the 677T allele was more pronounced in SAET (0.5 vs. 0.351 in controls, p <0.001) regardless of the karyotype status (aneuploidy vs. normal karyotype). In addition, the frequencies of the CA and CC haplotypes were significantly lower than in the control group (p = 0.021 and p = 0.001, respectively), whereas the frequency of the TC haplotype was significantly higher than in controls (p <0.0001). The presented findings indicate that only male probands contribute to the association of MTHFR mutations with fertility problems in grown adults and demonstrate a high prevalence of mutated MTHFR genotypes in SAET.

677TT Genotype Is Associated with Elevated Risk of Methotrexate (MTX) Toxicity in Juvenile Idiopathic Arthritis: Treatment Outcome, Erythrocyte Concentrations of MTX and Folates, and MTHFR Polymorphisms

Objective.To investigate whether methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and erythrocyte concentration of methotrexate (EMTX) could serve as predictors of methotrexate (MTX) efficacy and toxicity in patients with juvenile idiopathic arthritis (JIA).Methods.Genetic analyses and EMTX and folate assessment were performed in 69 patients with JIA aged 2.5–19.6 years (30 male) treated with MTX using a dose-escalation protocol and classified as full responders (disease inactivity; n = 51) or nonresponders (< 30% improvement in pediatric American College of Rheumatology-30 criteria while receiving ≥ 15 mg/m2/week parenteral MTX for at least 3 months; n = 18).Results.Nonresponders were treated with the higher median MTX dose (17.2 vs 12.6 mg/m2/week; p < 0.0001) and accumulated more EMTX (217 vs 106 nmol/l; p < 0.02) and erythrocyte folates (763 vs 592 nmol/l; p = 0.052) than responders. Analysis of MTHFR allele and genotype frequencies in relation to response failed to detect association. The frequency of any adverse effect was 29.4% in responders and 33.3% in nonresponders (p = 0.77). The frequency of 677T allele was elevated in patients with adverse effects (52.4% vs 20.9%; OR 3.88, 95% CI 1.8–8.6, p < 0.002). The probability of any adverse effect was significantly higher in patients with 677TT compared to the 677CC genotype (OR 55.5, 95% CI 2.9–1080, p < 0.001).Conclusion.MTHFR genotyping may have a predictive value for the risk of MTX-associated toxicity in patients with JIA. Despite the lack of therapeutic effect, nonresponders accumulated adequate concentrations of EMTX.

The Allele Frequencies of Three Polymorphisms in Genes Involved in Homocysteine Metabolism in a Group of Unrelated Healthy Singaporeans

The cystathionineβ-synthase (CBS) 844ins68 polymorphism, methionine synthase (MS) A2756G SNP, and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T SNP are associated with homocysteine (Hcy) level in humans. Elevated Hcy level is considered a risk factor for atherosclerotic diseases among Asian populations. Therefore, the three polymorphisms may vary the risk for developing such diseases in Singaporeans. In this study, the three polymorphisms were determined in a group of unrelated healthy Singaporeans (273 Chinese, 127 Indians, and 156 Malays). Regarding allele frequencies, Indians had the highest frequencies of the CBS insertion allele (2.0%) and the MS 2756G allele (26.4%), while Chinese had the highestMTHFR677T allele frequency (27.5%). In addition, theMTHFR677T allele was found significantly lower in Chinese males than in their female counterparts. As the CBS insertion allele was suggested to be associated with lower Hcy level, whereas the MS 2756G allele and theMTHFRT/T genotype were related to higher Hcy level, the MS A/G or G/G genotype and theMTHFRT/T genotype were considered double genetic risk factors for elevated Hcy level. The frequency of such double genetic risk was 0.7% (4 subjects) in the total population consisting of 3 Chinese (1.1%) and 1 Malays (0.6%). NoMTHFRT/T genotype was found in Indians. Such results suggested that Chinese could have higher Hcy levels than Malays while the situation for Indians was complicated. Since human Hcy levels are also affected by environmental factors, further studies are required to better evaluate the association between these three polymorphisms and Hcy levels and/or disease susceptibilities in Singaporeans.