Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Common 677C-->T mutation of the 5,10-methylenetetrahydrofolate reductase gene affects follicular estradiol synthesis. Hecht S et al. OBJECTIVE: To investigate the influence of the 5,10-methylenetetrahydrofolate reductase 677C-->T mutation on the E(2) synthesis in human granulosa cells (GCs). DESIGN: In vitro cell culture study. SETTING: Research laboratory of a university hospital. PATIENT(S): Follicular fluids (n = 139) and GCs (n = 66) were obtained from patients undergoing controlled ovarian hyperstimulation for IVF with or without ICSI. INTERVENTION(S): Granulosa cells were cultured for a total of 5 days. On day 3, the cells either were stimulated with recombinant (r-) FSH or r-LH (80 IU/L for 48 h) or were sham stimulated. MAIN OUTCOME MEASURE(S): Estradiol and protein content were measured in the pooled follicular fluids of each individual. At the end of each GC-culturing period, the concentrations of E(2) were measured in the supernatants of triplicate cultures by immunoassays. The 5,10-methylenetetrahydrofolate reductase 677C-->T genotype was determined by RFLP analysis. RESULT(S): The E(2)-protein ratio of homozygous T/T carriers was significantly lower compared with that of homozygous C/C individuals. Furthermore, basal and r-FSH- as well as r-LH-stimulated E(2) synthesis of GC obtained from homozygous T/T patients was significantly reduced, compared with GC from heterozygous C/T and homozygous C/C subjects. CONCLUSION(S): Decreased E(2) in follicular fluid and decreased E(2) synthesis of GC from homozygous T/T individuals suggest that reduced follicular E(2) is a result of impaired E(2) production of human GC.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Association of methylenetetrahydrofolate reductase gene C677T polymorphism with polycystic ovary syndrome risk: a systematic review and meta-analysis update. Fu LY 2013 et al. OBJECTIVES To re-estimate the association between methylenetetrahydrofolate reductase gene (MTHFR) C677T polymorphism and polycystic ovary syndrome (PCOS) risk by critically reviewing, analyzing and updating the current evidence. MTHFR C677T polymorphism has been studied as a possible risk factor for a variety of common conditions including heart disease, stroke and hypertension. Its association with PCOS was negative in a previous meta-analysis which had possible shortcomings. More studies have now been done but their results remain inconclusive. STUDY DESIGN Available case-control studies containing genotype frequencies of MTHFR C677T were chosen, and odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association. Statistical analyses were performed using software Review Manager (Version 5. 2) and Stata (Version 11.0). RESULTS Nine case-control studies including 638 PCOS and 759 healthy controls were identified. Meta-analysis showed a significant effect in the dominant model (TT+CT vs. CC: OR=1.65, 95%CI=1.28-2.12, P<0.0001) and heterozygote comparison (CT vs. CC: OR=1.83, 95%CI=1.17-2.87, P=0.008). In subgroup analysis stratified by ethnicity, MTHFR C677T variant was statistically significantly relevant to PCOS risk in European populations (TT+CT vs. CC: OR=2.16, 95%CI=1.50-3.12, P<0.0001; CT vs. CC: OR=2.11, 95%CI=1.15-3.87, P=0.02) but not in Asian populations (TT+CT vs. CC: OR=1.29, 95%CI=0.91-1.82, P=0.15; CT vs. CC: OR=1.31, 95%CI=0.91-1.90, P=0.15). CONCLUSIONS This meta-analysis indicates that the 677T allele increases PCOS susceptibility, and this relevance seems to be more intense in Europeans than in Asians. /////////////////////////

Species: human
Mutation name: None
type: naturally occurring
fertility: fertile
Comment: MTHFR polymorphisms C677T and A1298C and associations with IVF outcomes in Brazilian women. D'Elia PQ 2014 et al. The aim of this study was to investigate the association between MTHFR gene polymorphisms and IVF outcomes in Brazilian women undergoing assisted reproduction treatment. A prospective study was conducted in the Human Reproduction Department at the ABC University School of Medicine and the Ideia Fertility Institute between December 2010 and April 2012. The patient population was 82 women undergoing assisted reproduction cycles. The MTHFR polymorphisms C677T and A1298C were evaluated and compared with laboratory results and pregnancy rates. The C677T variant was associated with proportions of mature (P=0.006) and immature (P=0.003) oocytes whereas the A1298C variant was associated with number of oocytes retrieved (P=0.044). The polymorphisms, whether alone or in combination, were not associated with normal fertilization, good-quality embryo or clinical pregnancy rates. This study suggests that the number and maturity of oocytes retrieved may be related to the MTHFR polymorphisms C677T and A1298C. It is believed that folate has a crucial function in human reproduction and that folate deficiency can compromise the function of the metabolic pathways it is involved in, leading to an accumulation of homocysteine. The gene MTHFR encodes the 5-MTHFR enzyme, which is involved in folate metabolism, and C677T/A1298C polymorphisms of this gene are related to decreased enzyme activity and consequent changes in homocysteine concentration. Folate deficiency and hyperhomocysteinaemia can also compromise fertility and lead to pregnancy complications by affecting the development of oocytes, preparation of endometrial receptivity, implantation of the embryo and pregnancy. In folliculogenesis, hyperhomocysteinaemia can activate apoptosis, leading to follicular atresia and affecting the maturity of oocytes and the quality of embryos cultured in vitro. This study was performed to investigate the association between MTHFR polymorphisms and IVF outcomes in women undergoing assisted reproduction treatment. /////////////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Genetic polymorphism of Methylenetetrahydrofolate reductase is associated with insulin resistance in Egyptian women with polycystic ovary syndrome. M N AA et al. (2019) A common polymorphism (677C to T; Ala to Val) in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with decreased specific MTHFR activity and elevation of the homocysteine. to investigate the association between single nucleotide polymorphism (SNP) in MTHFR 677C>T gene and insulin resistance in women with polycystic ovary syndrome (PCOS). Subject& Methods Two-hundred patients with PCOS were included in this case- control study. 100 of them with insulin resistance and 100 without insulin resistance were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) RESULTS: The TT genotype for MTHFR 677C>T polymorphism was significantly more frequent in PCOS patients with insulin resistance than in PCOS patients without insulin resistance (19 vs. 6 %, p= 0.002), while no significant difference between both groups for CT and there was a statistically significant increase in the T allele in PCOS patients with insulin resistance as compared to PCOS patients without insulin resistance (p= 0.002, OR 1.95 and 95% CI: 1.29-2.93).As regard the relation between MTHFR 677C>T genotypes with the characteristics of insulin resistance in PCOS patients and we found that there was no significant difference in age, waist-hip ratio (WHR), and total testosterone between the different genotypes of MTHFR 677C>T polymorphism. The mean values of BMI and HOMA-IR were significantly higher in TT genotype of MTHFR 677C>T when compared to CC genotype in PCOS patients with insulin resistance (p < 0.001). We demonstrated an association of MTHFR 677C>T gene polymorphism with insulin resistance in Egyptian women with PCOS.//////////////////Association between a single nucleotide polymorphism in MTHFR gene and polycystic ovary syndrome. Choi SW et al. OBJECTIVE: The aim of the present study was to investigate whether there is an association between the C677T polymorphism in MTHFR and PCOS in a Korean population. STUDY DESIGN: The prevalence of MTHFR gene was compared between women with PCOS (n=227) and normal patients (n=115) using restriction fragment length polymorphism (RFLP) analysis. The HapAnalyzer was used to analyze the genotype of MTHFR polymorphism in PCOS and control subjects. We considered a p-value less than 0.05 as statistically significant. RESULTS: The frequency of C/C, C/T, and T/T genotype showed similar proportion between PCOS and control subjects. In addition, the frequencies of co-dominant (p-value=0.8334, odds ratio (OR)=1.04), dominant (p-value=0.8749, OR=0.96) and recessive alleles (p-value=0.5574, OR=1.22) did not show any association between PCOS and control subjects. CONCLUSION: Our data demonstrate that the C677T polymorphism of MTHFR gene is not associated with PCOS in a Korean population, suggesting that the C677T polymorphism in MTHFR may have different influences in various ethnic groups and diseases. Plasminogen Activator Inhibitor 1 and Methylenetetrahydrofolate Reductase Gene mutations in Iranian Women with Polycystic Ovary Syndrome. Idali F et al. PROBLEM: Mutations in genes related to thrombophilia and hypofibrinolysis have been associated with recurrent pregnancy loss (RPL) and polycystic ovary syndrome (PCOS). METHODS: Using PCR-RFLP, we investigated the frequencies of MTHFR (A1298C and C677T) as well as PAI-1 (-675 4G/5G) gene polymorphisms in 177 RPL and 100 control women. RPL women were stratified into 38 women with PCOS (RPL-PCOS), 33 with ovarian PCO (RPL-ovarian PCO), and 106 without PCOS (RPL). RESULTS: RPL, RPL-PCOS, and RPL-ovarian PCO groups showed significantly higher frequencies of MTHFR A1298C (P?

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Role of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in polycystic ovary syndrome risk. Wu JB et al. (2017) Polycystic ovary syndrome is one of the most frequently encountered endocrine malfunctions. Methylenetetrahydrofolate reductase (MTHFR) plays a vital role in folate metabolism, DNA methylation, and RNA synthesis. We carried out a study to investigate the association between MTHFR C677T and A1298C genetic variations and the risk of polycystic ovary syndrome in a Chinese population. We recruited 244 patients and 257 control subjects from an Inner Mongolian Medical University to this hospital-based, case-control study. The genotyping of the MTHFR C677T and A1298C polymorphisms was carried out using polymerase chain reaction coupled with restriction fragment length polymorphism. Using multiple logistic regression analysis, we found that the TT genotype and the T allele of MTHFR C677T carriers showed increased risk of polycystic ovary syndrome compared with the wild-type genotype or allele carriers. The adjusted ORs for the TT genotype and the T allele of MTHFR C677T were 1.84 (1.05-3.26) and 1.38 (1.06-1.81), respectively. Subjects carrying the CC genotype (OR = 3.98, 95%CI = 1.60-11.23) and the C allele (OR = 1.46, 95%CI = 1.07-2.00) of MTHFR A1298C had an elevated risk of polycystic ovary syndrome compared with the AA genotype and A allele carriers. In conclusion, our study suggests that the MTHFR C677T and A1298C polymorphisms may have contributed to the risk of polycystic ovary syndrome in the Chinese women investigated. Further research involving a greater number of individuals is warranted to confirm our results.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Methylenetetrahydrofolate reductase C677T polymorphism and the risks of polycystic ovary syndrome: an updated meta-analysis of 14 studies. Wang L et al. (2017) Some studies have reported an association between the Methylenetetrahydrofolate reductase (MTHFR) C667T genetic variant and risk of polycystic ovary syndrome (PCOS), although the results remain controversial. A systematic search was conducted on PubMed, Web of Science, EMBASE, Ovid, Chinese National Knowledge Databases and WanFang databases with relevant keywords. Fourteen studies of sixteen distinct populations involving 1478 PCOS cases and used to conduct a meta-analysis. The T allele was not significantly associated with increased risk of PCOS [OR: 1.08; 95% CI: 0.96-1.21]. In the stratified analysis by ethnicity, the T allele significantly increases risks for the Asian [OR = 1.31; 95% CI: 1.09-1.58] population. No significant associations were detected for the Middle Eastern population [OR = 1.26; 95% CI: 0.96-1.67] and the T allele was found to be protective in the Caucasian population [OR = 0.82; 95% CI: 0.68-0.99]. In conclusion, this meta-analysis suggests that MTHFR C667T variant can increase, decrease, or have no effect on the risks of PCOS depending on the ethnicity.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Methylenetetrahydrofolate reductase C677T polymorphism and the risks of polycystic ovary syndrome: an updated meta-analysis of 14 studies. Wang L et al. (2017) Some studies have reported an association between the Methylenetetrahydrofolate reductase (MTHFR) C667T genetic variant and risk of polycystic ovary syndrome (PCOS), although the results remain controversial. A systematic search was conducted on PubMed, Web of Science, EMBASE, Ovid, Chinese National Knowledge Databases and WanFang databases with relevant keywords. Fourteen studies of sixteen distinct populations involving 1478 PCOS cases and used to conduct a meta-analysis. The T allele was not significantly associated with increased risk of PCOS [OR: 1.08; 95% CI: 0.96-1.21]. In the stratified analysis by ethnicity, the T allele significantly increases risks for the Asian [OR = 1.31; 95% CI: 1.09-1.58] population. No significant associations were detected for the Middle Eastern population [OR = 1.26; 95% CI: 0.96-1.67] and the T allele was found to be protective in the Caucasian population [OR = 0.82; 95% CI: 0.68-0.99]. In conclusion, this meta-analysis suggests that MTHFR C667T variant can increase, decrease, or have no effect on the risks of PCOS depending on the ethnicity.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: None
Comment: MTHFR C677T polymorphism is associated with follicle-stimulating hormone levels and controlled ovarian hyperstimulation response: a retrospective study from the clinical database. Zeng S et al. (2019) To evaluate the impact of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with clinical data analysis in controlled ovarian hyperstimulation (COH) of infertile women in the Intravenous Infusion Safety Evaluation Center of Hunan Province, People's Republic of China. Genetic Association Study. Reproductive medicine clinical. This genetic association study included 722 infertile women who received the standard long treatment protocol with accessible and complete electronic medical records. None. The clinical parameters were obtained from the Intravenous Infusion Safety Evaluation center. Basal FSH levels in the TT group were significantly higher than those of the CC group. The FSH levels after down-regulation in the TT group were higher than those of CC/CT genotypes. The TT genotype patients received significantly higher total doses of GnRH agonist and FSH compared with CC/CT genotypes, whereas the total dose of hCG was higher in the CT genotypes compared with the CC/TT genotypes. Further association analysis between hormone levels and COH outcomes indicated significantly negative correlation of basal FSH levels with antral follicle count and number of oocytes as well as the down-regulation FSH levels with the number of metaphase II oocytes and oocytes. The MTHFR C677T polymorphism was associated with high doses of ovarian stimulation medications, as well as higher FSH levels. The negative correlation between FSH levels and the number of oocytes suggested that C677T polymorphism may play a role in the poor prognosis of COH oocytes. This needs to be studied in future prospective studies with longer follow-up.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: fertile
Comment: The implication of single-nucleotide polymorphisms in ovarian hyperstimulation syndrome. Ghaderian SMH et al. (2019) Ovarian hyperstimulation syndrome (OHSS) is an undesirable complication in the course of ovarian stimulation. This kind of stimulation is aimed at acquiring a sufficient number of high-quality oocytes in in vitro fertilization (IVF). Whereas the predisposition to OHSS could be impacted by genetic polymorphisms in susceptible genes, the present study has been jointly conducted with an Iranian cohort to scrutinize its relevant implication. Genomic DNA was extracted from blood samples of patients with a normal ovarian response (NOR) or with OHSS. Samples were analyzed to detect polymorphisms MTHFR rs1801131, MTHFR rs1801133, AMHR2 rs2002555, LHCGR rs2293275, PGR rs10895068, and SERPINE1 rs1799889. Variations of MTHFR, AMHR2, LHCGR, and PGR genes were significantly associated with the developing OHSS. After correction for multiple analysis, this difference was not evident for PGR genotypes. The polymorphic alleles of MTHFR (rs1801131 C-allele and rs1801133 T-allele), AMHR2 (rs2002555 G-allele), and LHCGR (rs2293275 G-allele) were significantly more prevalent among patients with OHSS compared to those in the NOR group. In contrast, the minor allele of PGR single-nucleotide polymorphism (SNP) (rs10895068, A-allele) was more prominent among patients with a NOR than those with OHSS. No significant difference was observed in genotypes or alleles of SERPINE1 rs1799889. The observations indicated that the minor alleles of MTHFR, AMHR2, and LHCGR genes could be considered an independent risk factor in susceptibility to OHSS. Nevertheless, polymorphic allele in the PGR rs10895068 SNP contributes to preventing OHSS occurrence. Therefore, it can be argued that these genes have a significant impact on OHSS.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Significant association between methylenetetrahydrofolate reductase gene C677T polymorphism with polycystic ovary syndrome risk: A meta-analysis update. Li Y et al. (2020) The methylenetetrahydrofolate reductase (MTHFR) may play a pathological role in polycystic ovary syndrome (PCOS). However, the conclusions of published reports on the relationship between the MTHFR C677T polymorphism and PCOS risk remain controversial.To derive a more precise estimation we performed a metaanalysis based on 22 studies that together included 2405 cases and 2419 controls. PubMed, EMBASE, WanFang and the Chinese National Knowledge Infrastructure databases were used to retrieve articles up to up to October 28, 2019. The crude odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated to evaluate the association.Metaanalysis results showed a significant association between the MTHFR C677T polymorphism and PCOS risk in 3 genetic models (allele model: OR = 1.40, 95% CI = 1.27-1.53; dominant model: OR = 1.47, 95% CI = 1.17-1.85); homozygous model: OR = 1.90, 95% CI = 1.55-2.32). Moreover, significant associations were observed when stratified by ethnicity, source of controls, etiology, and genotype methods.This metaanalysis suggests that the T-allele of the MTHFR C677T polymorphism is associated with an increased risk of PCOS, especially in Asians further studies with larger population sizes are needed to confirm these results.//////////////////