Discovery of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency in Individuals With Common Psychiatric Comorbidities: A Retrospective Case Review.

INTRODUCTION: A retrospective analysis was conducted of a data set collected in an outpatient behavioral health clinic to assess medication metabolism and methylenetetrahydrofolate reductase (MTHFR) and to see if there was a correlation with certain diagnoses and/or gender. METHOD: The outpatient routine completed genetic testing on their patients and the test results were later collected through a third-party company, which completed the pharmacogenomic test analyzing genetic variations in DNA, medication metabolism, and an MTHFR deficiency. RESULTS: This study reviewed 186 patients seen in an outpatient setting who were tested for an MTHFR deficiency and compared their psychiatric diagnoses and the number of failed medication attempts. Of those 186 patients, 77 had normal MTHFR enzyme function, 85 were found to have a moderate MTHFR deficiency, and 24 had a severe MTHFR deficiency. Those with a severe MTHFR deficiency had a higher number of medication trials as compared to those without the deficiency and there were overall more patients with a moderate MTHFR deficiency in this data set. CONCLUSION: Currently, MTHFR deficiency is not commonly tested due to lack of insurance coverage and provider knowledge, and due to the cost of the test itself. Thus, the diagnosis can often be missed.

Enhanced recovery in patients with gestational diabetes mellitus and MTHFR 677 TT genotype after taking high-dose folic acid supplements during mid-late pregnancy: an open-label interventional study.

Objective: To explore the relationship between folic acid supplementation and the recovery rate of gestational diabetes mellitus (GDM) in women with methylenetetrahydrofolate (MTHFR) 677 TT genotypes in mid-late pregnancy. Methods: 9, 096 pregnant women were recruited with their MTHFR gene genotyped. 5,111 women underwent a 75-g oral glucose tolerance test (OGTT) and 2,097 were confirmed with GDM. The association between MTHFR genotypes and GDM risk was estimated using logistic and log-binomial regression, with age and parity set as the covariates to control their confounding effects. Further assessment of GDM risk on glucose levels was done using the ANCOVA model. As an open-label intervention study, 53 GDM patients with TT genotype were prescribed 800µg/day of folic acid as the high-dose group, while 201 GDM patients were given 400µg/day as the standard-dose group at their 24-28 weeks of pregnancy. A rate ratio (RR) of GDM recovery was estimated at each available time point for both groups. The time-to-GDM persistence events were analyzed with the Kaplan-Meier method and Cox-regression model. The trend of glucose levels over time was estimated using the linear model. Results: MTHFR 677 TT genotype has no significant association with the glucose levels and GDM risk, with an adjusted OR of 1.105 (95% CI 0.853, 1.431; p=0.452) and an adjusted PR of 1.050 (95% CI 0.906, 1.216; p=0.518) compared to the wildtype CC group. Patients in the high-dose group (n=38; 15 drop-outs; 40.69 days (95% CI 33.22, 48.15)) recovered from GDM approximately 27 days faster than those in the standard-dose group (n=133; 68 drop-outs; 68.09 days (95% CI 63.08, 73.11)). Concomitantly, the RR of GDM recovery rose and reached 1.247 (95% CI 1.026, 1.515) at 100 days of treatment with the standard-dose group as reference. Conclusion: High-dose folic acid supplement intake in mid-late pregnancy is associated with faster GDM relief in patients with MTHFR 677 TT genotype compared to the standard dose, which would be served as a novel and low-cost alternative therapy for the treatment of GDM.

Contribution of Genetic Test to Early Diagnosis of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency: The Experience of a Reference Center in Southern Italy.

BACKGROUND: the deficiency of 5,10-Methylenetetrahydrofolate reductase (MTHFR) constitutes a rare and severe metabolic disease and is included in most expanded newborn screening (NBS) programs worldwide. Patients with severe MTHFR deficiency develop neurological disorders and premature vascular disease. Timely diagnosis through NBS allows early treatment, resulting in improved outcomes. METHODS: we report the diagnostic yield of genetic testing for MTHFR deficiency diagnosis, in a reference Centre of Southern Italy between 2017 and 2022. MTHFR deficiency was suspected in four newborns showing hypomethioninemia and hyperhomocysteinemia; otherwise, one patient born in pre-screening era showed clinical symptoms and laboratory signs that prompted to perform genetic testing for MTHFR deficiency. RESULTS: molecular analysis of the MTHFR gene revealed a genotype compatible with MTHFR deficiency in two NBS-positive newborns and in the symptomatic patient. This allowed for promptly beginning the adequate metabolic therapy. CONCLUSIONS: our results strongly support the need for genetic testing to quickly support the definitive diagnosis of MTHFR deficiency and start therapy. Furthermore, our study extends knowledge of the molecular epidemiology of MTHFR deficiency by identifying a novel mutation in the MTHFR gene.

Genetic Determinants of Cardiovascular Disease: The Endothelial Nitric Oxide Synthase 3 (eNOS3), Krüppel-Like Factor-14 (KLF-14), Methylenetetrahydrofolate Reductase (MTHFR), MiRNAs27a and Their Association with the Predisposition and Susceptibility to Coronary Artery Disease.

Coronary artery disease (CAD) is an important cause of death worldwide. CAD is caused by genetic and other factors including hypertension, hyperlipidemia, obesity, stress, unhealthy diet, physical inactively, smoking and Type 2 diabetes (T2D). The genome wide association studies (GWASs) have revealed the association of many loci with risk to diseases such as cancers, T2D and CAD. Nitric oxide (NO) is a potent vasodilator and is required for normal vascular health. It is produced in the endothelial cells in a reaction catalyzed by the endothelial NO synthase (eNOS). Methylenetetrahydrofolate reductase (MTHFR) is a very important enzyme involved in metabolism of folate and homocysteine, and its reduced function leads to cardiovascular disease. The Krüppel-like factor-14 (KLF-14) is an important transcriptional regulator that has been implicated in metabolic syndrome. MicroRNA (MiRNAs) are short non-coding RNAs that regulate the gene expression of proteins involved in important physiological processes including cell cycle and metabolism. In the present study, we have investigated the potential impact of germline pathogenic variants of endothelial eNOS, KLF-14, MTHFR, MiRNA-27a and their association with risk to CAD in the Saudi population. Methods: Amplification Refractory Mutation System (ARMS) PCR was used to detect MTHFR, KLF-14, miRNA-27a and eNOS3 genotyping in CAD patients and healthy controls. About 125 CAD cases and 125 controls were enrolled in this study and statistical associations were calculated including p-value, risk ratio (RR), and odds ratio (OD). Results: There were statistically significant differences (p < 0.05) in genotype distributions of MTHFR 677 C>T, KLF-14 rs972283 G>A, miRNAs27a rs895819 A>G and eNOS3 rs1799983 G>T between CAD patients and controls. In addition, our results indicated that the MTHFR-TT genotype was associated with increased CAD susceptibility with an OR 2.75 (95%) and p < 0.049, and the KLF14-AA genotype was also associated with increased CAD susceptibility with an OR of 2.24 (95%) and p < 0.024. Moreover, the miRNAs27a-GG genotype protects from CAD risk with an OR = 0.31 (0.016), p = 0.016. Our results also indicated that eNOS3 -GT genotype is associated with CAD susceptibility with an OR = 2.65, and p < 0.0003. Conclusion: The MTHFR 677C>T, KLF14 rs972283 G>A, miRNAs27a A>G, and eNOS3 rs1799983 G>T genotypes were associated with CAD susceptibility (p < 0.05). These findings require verification in future large-scale population based studies before these loci are used for the prediction and identification of individuals at risk to CAD. Weight control, physical activity, and smoking cessation are very influential recommendations given by clinicians to the at risk individuals to reduce or delay the development of CAD.

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

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.

A Study of the MTHFR Gene Prevalence in a Rural Tennessee Opioid Use Disorder Treatment Center Population.

Background: Opioid Use Disorder (OUD) has been linked to dopamine and the neurological reward centers. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in the production of many neurotransmitters such as dopamine. As such, MTHFR variants that lead to decreased production of neurotransmitters may play a role in OUD. However, lacunae exist for characterizing the prevalence of the MTHFR mutations in an OUD population. The objective of this study was to determine prevalence of the MTHFR gene mutations in a rural Tennessean population with OUD. Methods: This study was a retrospective cohort of individuals with OUD that evaluated the prevalence of MTHFR variants. Patients were categorized as normal, homozygous C677T, heterozygous C677T, homozygous A1298C, or heterozygous A1298C. The primary outcome was a qualitative comparison of the prevalence of each of the MTHFR variants in our cohort to the publicly reported MTHR polymorphism prevalence. Secondary outcomes include race and ethnicity differences as well as stimulant use differences for each of the variants. Results: A total of 232 patients undergoing care for opioid use disorder were included in the study. Of those included, 30 patients had a normal MTHFR allele and 202 had a variant MTHFR allele. Overall, the prevalence of any MTHFR variant was 87.1% (95% CI 82.6-91.4%). When comparing those with a normal MTHFR allele to those with any MTHFR variant, there was no difference in age, sex, race and ethnicity, or stimulant use. Conclusion: The overall prevalence of MTHFR variants in patients with opioid use disorders is high.

Genetic Markers of Therapeutic Efficacy of Methotrexate in Patients with Psoriasis.

We studied the effect of C677T and A1298C polymorphisms of the MTHFR gene and 2R/3R polymorphisms of the TYMS gene on the sensitivity to methotrexate in patients with psoriasis (n=139). It was shown that genotype 3R/3R TYMS (OR 8.86, 95%CI 2.00-39.22) and complex genotypes MTHFR1298:A;TYMS:3R (OR 8.20, 95%CI 2.36-28.48) and MTHFR677:C;TYMS:3R (OR 5.40, 95%CI 1.95-14.94) were associated with sensitivity to methotrexate, while genotype 2R/2R TYMS (OR 8.20, 95%CI 2.36-28.48) and complex genotypes MTHFR1298:C;MTHFR677:T;TYMS:2R (OR 0.18, 95%CI 0.06-0.56) and MTHFR1298:C;MTHFR677:T (OR 0.23, 95%CI 0.09-0.59) were associated with resistance to methotrexate. The results can be used for preventive assessment of the effectiveness of methotrexate treatment in patients with psoriasis.

Relationship between MTHFR Gene Polymorphisms and Gastrointestinal Tumors Development: Perspective from Eastern Part of Turkey.

BACKGROUND: Gastric and esophageal cancers are 2 of the most prevalent cancer types worldwide. Polymorphisms in the genes that code the methylenetetrahydrofolate reductase (MTHFR) enzyme increase the formation of both cancer types. In this study, it was aimed to research the relationship between the existence of MTHFR C677T and A1298C polymorphisms in patients with gastric and esophageal cancer and the lifespans of patients. METHODS AND MATERIALS: This prospective study was performed at Van Yuzuncu Yil University. Included in the study were 30 patients with esophageal tumors, 70 patients with gastric tumors, and 61 healthy volunteers. From each of the patients, 5 mL of blood was drawn. DNA was isolated via kits with spin-column technology. RESULTS: It was concluded that the risk of developing gastric cancer was 4.13 times higher in individuals who had the AC genotype of the A1298C polymorphism when compared to those who had the AA genotype, while the risk was 2.91 times higher in individuals who had the CC genotype when compared to those who had the AA genotype (P = 0.001, P = 0.027). Carriers of the AC genotype of the A1298C polymorphism had 2.89 times higher risk of developing esophageal cancer when compared to those who had the AA genotype (P = 0.033). It was determined that individuals who had the 1298 CC genotype were not at higher risk of developing esophageal cancer when compared to those with the AA genotype (P = 0.863). It was concluded that individuals who had the TT genotype of the C677T polymorphism were not at higher risk of developing gastric and esophageal cancers when compared to those who had the 677CC genotype (P > 0.05). There was no difference in terms of the life spans of the patients with regards to the genotypes (P > 0.05). CONCLUSION: The results showed that the A1298C polymorphism on the MTHFR gene can be a risk factor for gastric and esophageal cancer in eastern Turkey. These polymorphisms may have no effect on the life spans of the patients.

Association of MTHFR and TYMS gene polymorphisms with the susceptibility to HCC in Egyptian HCV cirrhotic patients.

Identification of host genetic factors influencing the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection may help to refine patients' selection to benefit from specific preventative measures and/or adapted screening policies. Thus, this study aimed to investigate the association of MTHFR c.677C > T and c.1298A > C in addition to TYMS 3'-UTR 6-bp ins/del polymorphisms with the susceptibility to HCV-related HCC in an Egyptian population. Polymerase chain reaction-restriction fragment length polymorphism was performed to genotype the polymorphisms in 194 HCV-infected patients subdivided into liver cirrhotic (LC, n = 104) and HCC (n = 90) patients as well as 100 healthy subjects. In healthy controls, the MTHFR c.677C > T polymorphism under the homozygous and recessive models (p = 0.005) and the c.1298A > C polymorphism under all the tested genetic models (p-values range from < 0.001 to 0.007) were associated with an increased risk of HCC. In LC patients, the MTHFR c.677C > T polymorphism under the homozygous, dominant, and recessive models (p-values range from 0.001 to 0.007), as well as MTHFR c.1298A > C under the homozygous model only (p = 0.014), increased the susceptibility to HCC. The C/C and T/C haplotypes of MTHFR c.677C > T and MTHFR c.1298A > C polymorphisms were contributed to an increased risk of healthy subjects to develop HCC (p-values range from < 0.001 to 0.015), while only the T/C haplotype was associated with the progression of HCC in LC patients (p = 0.001). In conclusion, MTHFR c.677C > T and c.1298A > C in addition to their haplotypes may contribute to the development of HCV-related HCC in an Egyptian population. These findings may aid in the early diagnosis and management of HCC.

Severe Adverse Toxic Effects of Low-Dose Methotrexate Treatment on an Ectopic Pregnancy Patient With Methylenetetrahydrofolate Reductase Mutations: A Case Report.

Background: Low-dose methylenetetrahydrofolate (LD-MTX) has been widely used for the treatment of the ectopic pregnancy (EP) for many decades, and related severe adverse toxic effects are rare. Current studies have shown that the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene can decrease the MTX clearance, leading to the metabolite accumulation. However, there is a lack of literature report on an MTHFR gene polymorphism associated with adverse toxic effects resulting from the use of LD-MTX in an EP. Case Presentation: We report a rare case of a 38-year-old female who developed persistent fever, grade IV myelosuppression, skin lesions, mucositis, and liver injury after single dose of LDMTX to treat EP. The personalized genetic testing showed that MTHFR TT (677C>T) and MTHFR AA (1298A>C) were detected. Gradually, the symptoms improved after calcium leucovorin (CF) rescue, continuous renal replacement therapy (CRRT), promoting blood system regeneration, and multiple supportive treatments. Conclusion: This is the first report on the serious adverse toxic effects of LD-MTX on an EP patient with MTHFR mutations. We aim to alert obstetricians and gynecologists to this rare condition. The unexpected life-threatening toxicity with LD-MTX should be highly considered and recognized early. In particular, some easily overlooked gastrointestinal, skin, and mucosal symptoms occur earlier than severe myelosuppression. When toxic effects are suspected, detecting the polymorphisms of an MTHFR gene and monitoring MTX concentration in blood could assist us to formulate individualized and active treatments.

Study on Relationships of Tumor Status and Gene Polymorphism With Blood Concentration of MTX and Toxicities in 63 Pediatric Mature B Cell Lymphoma in Chinese Population.

OBJECTIVE: This study investigated the relationships of tumor status (stage, renal involvement, bone marrow status, bulky disease, liver function), tumor gene polymorphism, and methotrexate (MTX) dosage (stratified by treatment group) with blood MTX levels and adverse reactions (ADR). METHODS: We retrospectively reviewed 63 mature B cell lymphoma patients who were treated in our center. Genotyping of the MTHFR 677 and SLCO1B1 genes was carried out, and the relationships between tumor status, polymorphism of the genes, MTX level, and ADR were analyzed. RESULTS: Altogether, 63 children were included. The mean blood MTX concentration was 0.25 ± 0.2 umol/L at 45 h. Liver dysfunction and bulky disease were both correlated with MTX level (both P < 0.05). ADRs were higher among patients with blood MTX > 0.5 mmol/l at 45 h than for the groups with lower blood MTX. The MTHFR 677 CT genotype was correlated with liver function damage (P = 0.04); the rs11045879 locus CC genotype of SLCO1B1, stage IV, and bulky disease at the time of diagnosis were correlated with 4° neutropenia (P < 0.05). Stage IV, bulky disease, leukemia stage at the time of diagnosis, and C2 treatment group were correlated with severe anemia (P < 0.05). Stage IV, bulky disease, leukemia stage, renal invasion at the time of diagnosis, and C2 treatment group were associated with severe thrombocytopenia (P < 0.05). Bulky disease and renal invasion at the time of diagnosis were associated with severe mucositis and severe infection (P < 0.05). CONCLUSION: Taken together, our data demonstrate that gene polymorphism, MTX levels, tumor status, and treatment group might be useful to optimize MTX therapy and estimate toxicity.

Clinical presentation of seven patients with Methylenetetrahydrofolate reductase deficiency.

Methylenetetrahydrofolate reductase deficiency; MTHFR (MIM 236250) is widely studied with more than 200 reported cases up to our knowledge from pediatrics to adult patients. Clinical presentation of MTHFR deficiency has a wide spectrum and its severity correlates with the degree of the enzyme activity. We report here seven pediatric cases with variable presentations including apnea at early infancy, in addition to hydrocephalus that needed drainage.

Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate.

Adequate levels of folates are essential for homeostasis of the organism, prevention of congenital malformations, and the salvage of predisposed disease states. They depend on genetic predisposition, and therefore, a pharmacogenetic approach to individualized supplementation or therapeutic intervention is necessary for an optimal outcome. The role of folates in vital cell processes was investigated by translational pharmacogenetics employing lymphoblastoid cell lines (LCLs). Depriving cells of folates led to reversible S-phase arrest. Since 5,10-methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in the biosynthesis of an active folate form, we evaluated the relevance of polymorphisms in the MTHFR gene on intracellular levels of bioactive metabolite, the 5-methyltetrahydrofolate (5-Me-THF). LCLs (n = 35) were divided into low- and normal-MTHFR activity groups based on their genotype. They were cultured in the presence of folic acid (FA) or 5-Me-THF. Based on the cells' metabolic activity and intracellular 5-Me-THF levels, we conclude supplementation of FA is sufficient to maintain adequate folate level in the normal MTHFR activity group, while low MTHFR activity cells require 5-Me-THF to overcome the metabolic defects caused by polymorphisms in their MTHFR genes. This finding was supported by the determination of intracellular levels of 5-Me-THF in cell lysates by LC-MS/MS. FA supplementation resulted in a 2.5-fold increase in 5-Me-THF in cells with normal MTHFR activity, but there was no increase after FA supplementation in low MTHFR activity cells. However, when LCLs were exposed to 5-Me-THF, a 10-fold increase in intracellular levels of this metabolite was determined. These findings indicate that patients undergoing folate supplementation to counteract anti-folate therapies, or patients with increased folate demand, would benefit from pharmacogenetics-based therapy choices.

Medical Decision Support to Reduce Unwarranted Methylene Tetrahydrofolate Reductase (MTHFR) Genetic Testing.

Most major national medical associations have advised against routine MTHFR testing since at least 2013. However, many providers continue to order this unwarranted genetic test. This study assessed the efficacy of an electronic best practice alert to aid ordering providers. We tracked the rate of MTHFR tests ordered per 1 million patients in the twelve months before and after the implementation of an alert that suggested an alternative test. Associated factors including the ordering department, diagnosis, patient sex, and patient age were also analyzed. Chi square analysis was used to compare the difference between pre- and post-alert test ordering rates. A total of 997 MTHFR analysis were ordered in Southern California Kaiser Permanente from January 2017 through December 2018. Overall, the average MTHFR monthly test ordering rates dropped significantly from 12.93 per million patients in 2017 to 7.08 per million patients in 2018 (p = 0.0056). However, testing rates in children were unchanged and, in some associated diagnoses, such as psychiatric illnesses and neurodevelopmental conditions, the testing rates increased. Recommending an alternate test in lieu of the unwarranted one significantly reduced the overall rate of MTHFR testing. The alert was most effective for specialties and diagnoses where MTHFR was historically medically indicated. This suggests such alerts are an effective intervention that health care systems can implement to serve as an educational update and to reduce unwarranted genetic testing.

Association of methylenetetrahydrofolate reductase C677T and reduced-f carrier-1 G80A gene polymorphism with preeclampsia in Sudanese women.

Purpose: To assess the associations between preeclampsia, methylenetetrahydrofolate reductase (MTHFR) C677T, and reduced folate carrier-1 (RFC-1) G80A gene polymorphism in Sudanese women.Methods: A matched (for age and parity) case-control study was conducted in a tertiary hospital (Saad Abualila) in Khartoum, Sudan during February to September 2018. The cases were women with preeclampsia and healthy pregnant women were the controls (160 women in each arm of the study). Genotyping for MTHFR C677T and RFC-1 G80A was performed by polymerase chain reaction-restriction fragment length polymorphism.Results: . . The MTHFR C677T variation was significantly more frequent in women with preeclampsia (16.2%) than in healthy pregnant women (1.8%) (OR = 10.1, 95% CI = 3.0-34.2, P < 0.001). There was borderline significance in the RFC-1 G80A variation, which was present in 2.50% of women with preeclampsia, but was not found in healthy pregnant women (P = 0.052).Conclusions: A higher prevalence of MTHFR C677T polymorphism in women with preeclampsia compared with healthy pregnant women suggests involvement of this variation in preeclampsia in Sudan.

Folic Acid Fortification and Neural Tube Defect Risk: Analysis of the Food Fortification Initiative Dataset.

The United States implemented mandatory fortification of cereal grains with folic acid in 1998 to prevent neural tube defects (NTDs) during pregnancy. The health benefits of folate (vitamin B9) are well documented; however, there are potential risks of exceeding the upper tolerable limit, particularly in vulnerable populations. We conducted a population-based analysis of the Food Fortification Initiative dataset to determine the strength of the evidence regarding reports of decreased NTDs at the national level in response to mandatory folic acid fortification of cereal grains. We found a very weak correlation between NTD prevalence and the level of folic acid fortification, irrespective of the cereal grain fortified (wheat, maize or rice). Stratification of the data based on socioeconomic status (SES) indicated a strong linear relationship between reduced NTDs and better SES. We conclude that national fortification with folic acid is not associated with a significant decrease in the prevalence of NTDs at the population level.

A meta-analysis on associations of FTO, MTHFR and TCF7L2 polymorphisms with polycystic ovary syndrome.

BACKGROUND: We aimed to better clarify the relationship between FTO/MTHFR/TCF7L2 polymorphisms and PCOS in a larger combined population by performing a meta-analysis. METHODS: Eligible articles were retrieved from Pubmed, Embase, Web of Science and CNKI. Review Manager Version was used to perform statistical analyses. RESULTS: Forty-six studies were included for this meta-analysis. FTO rs9939609 polymorphism was found to be significantly associated with PCOS under dominant, recessive, over-dominant and allele comparisons, MTHFR rs1801131 polymorphism was found to be significantly associated with PCOS under recessive and allele comparisons, and MTHFR rs1801133 polymorphism was also found to be significantly associated with PCOS under dominant, recessive and allele comparisons in general population. In subgroup analyses, we found that positive results were mainly driven by the Asians. CONCLUSIONS: Collectively, this meta-analysis proved that FTO rs9939609, MTHFR rs1801131 and MTHFR rs1801133 polymorphisms may serve as predisposing factors of PCOS, especially for Asians.

Associations between folate metabolism enzyme polymorphisms and breast cancer: A meta-analysis.

We performed this meta-analysis to explore associations between folate metabolism enzyme polymorphisms and breast cancer (BC) in a larger pooled population. Systematic literature research was performed to identify eligible studies for pooled analyses. Totally 92 genetic association studies were included for analyses. The pooled analyses revealed significant findings for MTRR rs1801394 polymorphism in South Asians, for MTR rs1805087 polymorphism in Caucasians and East Asians, and for MTHFR rs1801133 polymorphism in East Asians. In conclusion, the present meta-analysis indicated that MTRR rs1801394, MTR rs1805087, and MTHFR rs1801133 polymorphisms could be used to identify individuals at high risk of developing BC.

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in breast cancer: a Sardinian preliminary case-control study.

Two common polymorphisms in the MTHFR gene, C677T and A1298C, are associated with reduced enzyme activity and may be associated with breast cancer susceptibility. We performed a case-control study to investigate the association between the two SNPs in the MTHFR gene and risk of breast cancer. In total, 58 breast cancer patients and 58 unaffected controls were enrolled in the study. Polymerase chain reaction/restriction fragment length polymorphism technique (PCR-RFLP) was conducted to determine the genotypes. No significant differences were found in the genotypes of the two polymorphisms of the MTHFR gene between cases and controls. The OR and 95% CI for the 677CC, 677CT and 677TT genotypes were 1.00, 0.95 (0.39-2.31) and 0.87 (0.27-2.80), respectively; those of the 1298AA, 1298AC and 1298CC genotypes were 1.00, 0.59 (0.26-1.36) and 0.78 (1.32-4.66) respectively. Furthermore, it has been shown in patients with breast cancer a risk of presenting with an aggressive biophenotype about twice or three times higher in the presence of the C677T and A1298C polymorphisms, respectively. Finally, the A1298Cpolymorphism is significantly associated with increased recurrence risk of lymph node-positive breast cancer. Our study has not shown a significant association between MTHFR gene polymorphisms and breast cancer risk. However, it highlighted the key-role played by the presence of mutant alleles for both polymorphisms in increasing the risk of developing more aggressive phenotypes; moreover, specifically in A1298C, it might also lead to a higher risk of developing lymph node metastasis.

Correlation between MTHFR polymorphisms and glaucoma: A meta-analysis.

BACKGROUND: Whether methylenetetrahydrofolate reductase (MTHFR) polymorphisms are implicated in glaucoma remains controversial. Therefore, we performed this study to better assess the relationship between MTHFR polymorphisms and the likelihood of glaucoma. METHODS: A systematic research of PubMed, Medline, and Embase was performed to retrieve relevant articles. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 18 studies with 7,168 participants were analyzed. In overall analyses, a significant association with the likelihood of glaucoma was detected for the rs1801133 polymorphism in dominant (p = 0.04, OR = 0.90, 95%CI 0.81-1.00) and allele (p = 0.02, OR = 0.91, 95%CI 0.84-0.98) comparisons. Further, subgroup analyses by ethnicity revealed that both rs1801131 and rs1801133 polymorphisms were significantly associated with the likelihood of glaucoma in West Asians. However, no positive results were detected for two investigated polymorphisms in East Asians and Caucasians. CONCLUSION: Our findings indicated that rs1801131 and rs1801133 polymorphisms may serve as genetic biomarkers of glaucoma in West Asians.