Methylenetetrahydrofolate Reductase C677T Gene Research Articles

MTHFRC 677T Gene Polymorphism and Homocysteine in North China Patients with Varicocele

To investigate the correlation between methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism, homocysteine, and male infertility with varicocele in North China. One Hundred infertile males with varicocele (VC; grade II-III, VC group) and 100 healthy males with normal semen parameters and no varicocele (NC group) were recruited for PCR microarray, blood and semen testing. Compared with the CC genotype in the NC group, the TT genotype in the NC group and the CC genotype in the VC group showed no significant changes in sperm motility (P=0.191; P=0.130), sperm density (P=0.591, P=0.643), plasma homocysteine level (P=0.511; P=0.677), and seminal plasma MDA (P=0.752; P=0.451). In contrast, VC patients with the TT genotype had higher plasma homocysteine level and seminal plasma MDA levels (P <0.001), lower partial pressure of oxygen in seminal pulse (PO2; P <0.001) and poorer sperm quality (P <0.001), as compared with the CC genotype. This suggests that MTHFR C677C>T may not be a risk factor for male Varicocele in North China. However, this may affect the oxidative stress associated with homocysteine expression, which in turn affects semen parameters in VC patients. Larger studies are needed to validate our findings.

MTHFR C677T Gene Polymorphism and Association with Disorders

The Methylenetetrahydrofolate reductase (MTHFR) is a general and important enzyme in human cells, which is responsible for the metabolism reactions of homocysteine and folate. The genetic material for MTHFR enzyme synthesis is situated on 1 chromosome p arm in the 1p36.3 position. A lot of single nucleotide mutations have been identified in this mentioned locus, but among them well-studied is the C677T gene mutation. The C677T/MTHFR polymorphisms impact MTHFR enzyme activity, leading to alterations in methionine and folate metabolism, homocysteine levels, and in most cases subsequent effects on DNA methylation. This literature review compiles information about the MTHFR C677T polymorphism and explores its potential association with various complex, multifactorial disorders, such as cancer, cardiovascular complications, neurological conditions, and diabetes mellitus, among others. The review synthesizes findings from diverse global populations, providing valuable insights for master's and doctorate students, as well as researchers specializing in this field.

Relationship between methylenetetrahydrofolate reductase C677T gene polymorphism and neutrophil gelatinase-associated lipocalin in early renal injury in H-type hypertension

ObjectiveTo analyse the relationship between the polymorphisms of the H-type hypertensive methylenetetrahydrofolate reductase (MTHFR) C677T gene and neutrophil gelatinase-associated lipocalin (NGAL) in early kidney injury.MethodA total of 279 hospitalised patients with hypertension were selected and grouped according to their homocysteine (Hcy) level. If their blood Hcy level was ≥ 10 µmol/L they were assigned to the H-type hypertensive group, and if it was < 10 µmol/L they were assigned to the non-H-type hypertensive group. Blood lipid indexes, renal function indexes and blood glucose indexes were collected, and the differences between the two groups were compared. Furthermore, MTHFR C677T genotype distribution and allele frequency and Hcy level of MTHFR C677T genotype were compared, and logistic multiple regression analysis was conducted for the correlation of different genotypes of MTHFR C677T and the early kidney injury marker NGAL.ResultsIn the non-H-type hypertensive group, the levels of Hcy and NGAL, cystatin, blood urea nitrogen, serum creatinine, uric acid, serum β2-microglobulin and urinary microalbumin-to-creatinine ratio increased significantly, and the glomerular filtration rate level decreased significantly, when compared with the H-type hypertensive group, with statistical differences (p < 0.05). The H-type hypertensive group and the non-H-type hypertensive group had significant differences in the CC, CT and TT genotypes and allele frequencies at the MTHFR C677T locus. The MTHFR C677T gene mutation rate of the H-type hypertensive group was significantly higher than that of the non-H-type hypertensive group. The H-type hypertensive group had higher levels of the TT genotype and CT genotype Hcy. There was a statistical difference (p < 0.05).ConclusionMethylenetetrahydrofolate reductase C677T polymorphism is correlated with the Hcy level, and its gene polymorphism will affect the Hcy level. Methylenetetrahydrofolate reductase C677T polymorphism has an interactive effect with NGAL. Screening NGAL and reducing Hcy levels are valuable methods for the prevention and treatment of early renal injury in patients with H-type hypertension and help improve the prognosis of patients and their quality of life.

MTHFR Gene C677T Polymorphism (rs1801133) and Susceptibility to Colorectal Polyps in an Azerbaijani Population.

Understanding the relationships between the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, colorectal polyps, and CRC risk can aid in advancing personalized medicine approaches in CRC prevention. The aim of the current study is to identify the association of C677T polymorphism of the MTHFR gene with the risk of colorectal polyps in the Azerbaijani population. This study included 125 patients with colon polyps and 155 healthy individuals as a control group. DNA was extracted from venous blood samples obtained from patients and healthy individuals, and the results were analyzed through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and agarose gel electrophoresis. Wild-type, heterozygote, and homozygous mutant were revealed within 69 (55.2%), 49 (39.2%), and 7 (5.6%) patients and within 100 (64.5%), 45 (29%), and 10 (6.5%) healthy controls, respectively. However, no significant statistical associations were observed between CT and TT genotypes, dominant (CC vs. CT + TT) and recessive (CC + CT vs. TT) models, and the mutant T allele and disease risk. There were also no significant differences between patients and controls regarding age, sex, smoking and alcohol use. Our research did not reveal any significant association between the MTHFR C677T polymorphism and susceptibility to colorectal polyps in the Azerbaijan population.

MTHFR gene polymorphisms and susceptibility to myocardial infarction: Evidence from meta-analysis and trial sequential analysis

BackgroundThis meta-analysis aimed to provide a comprehensive assessment of the association between Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms, specifically C677T and A1298C, and the susceptibility to myocardial infarction (MI). MethodsA systematic literature search was conducted in MEDLINE, Web of Science, and Scopus until April 2023 to identify studies investigating the relationship between MTHFR gene polymorphisms (C677T and A1298C) and the risk of MI. ResultsThe analysis included 66 studies involving 16,860 cases and 20,403 controls for the C677T polymorphism and 18 studies comprising 3162 cases and 3632 controls for the A1298C polymorphism. Significant associations were observed between the C677T polymorphism and MI risk in various genetic models: dominant (OR = 1.16, 95 % CI = 1.06–1.28, P = 0.008), recessive (OR = 1.20, 95 % CI = 1.12–1.28, P < 0.001), allelic (OR = 1.13, 95 % CI = 1.06–1.21, P < 0.001), TT vs. CC (OR = 1.19, 95 % CI = 1.05–1.36, P < 0.001), and CT vs. CC (OR = 1.11, 95 % CI = 1.02–1.21, P = 0.01). Furthermore, an overall analysis indicated a marginally significant association between the A1298C polymorphism and MI risk in the recessive model (OR = 1.27, 95 % CI = 1.06–1.51, P = 0.008), allelic model (OR = 1.18, 95 % CI = 1.01–1.39, P = 0.03), and CC vs. AA model (OR = 1.22, 95 % CI = 1.01–1.47, P = 0.04). Meta-regression analysis revealed that none of the potential factors contributed to the observed heterogeneity. ConclusionsThis meta-analysis revealed an association between MTHFR gene C677T and A1298C polymorphisms and the risk of MI.

Association between MTHFR gene C677T polymorphism and gestational diabetes mellitus in Chinese population: a meta-analysis.

The relationship of the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with the incidence of gestational diabetes mellitus (GDM) in the Chinese population remains controversial. This study aimed to further clarify the effect of the MTHFR gene C677T polymorphism on GDM risk among Chinese pregnant women based on current evidence. Several databases were searched up to July 29, 2023 for relevant case-control studies. The numbers of patients with and without the T allele of the MTHFR gene C677T polymorphism in the GDM and control groups were determined, and all statistical analyses were performed by RevMan 5.3 software and STATA 15.0 software. Trial sequential analysis (TSA) was performed by TSA version 0.9 beta software to determine the required information size. A total of 17 case-control studies involving 12345 Chinese participants were included. The pooled results demonstrated that the T allele of the MTHFR gene C677T polymorphism was significantly associated with an increased risk of GDM, which was manifested by the five gene models of the MTHFR C677T polymorphism [T vs. C: odds ratio (OR)=1.59, P=0.03; TT vs. CC: OR=2.24, P<0.001; TC vs. CC: OR=1.28, P=0.05; (TT+TC) vs. CC: OR=1.55, P=0.003; TT vs. (TC+CC): OR=1.89, P<0.001]. Subgroup analysis based on the regions indicated that the significant relationship between the T allele of the MTHFR gene C677T polymorphism and an increased risk of GDM was detected only among the southern population [T vs. C: OR=1.62, P=0.09; TT vs. CC: OR=2.22, P=0.004; TC vs. CC: OR=1.17, P=0.28; (TT+TC) vs. CC: OR=1.43, P=0.03; TT vs. (TC+CC): OR=1.97, P=0.006]. TSA plots showed that the information sizes for the association between the MTHFR gene C677T polymorphism and GDM risk were sufficient in the homozygote (TT vs. CC) and recessive (TT vs. TC+CC) models. The MTHFR gene C677T polymorphism is closely related to susceptibility to GDM in the southern Chinese population, and the C-T mutation serves as an important genetic risk factor for GDM. More well-designed large case-control studies are needed to further confirm the above findings.

Investigating the Association of MTHFR C677T Gene Polymorphism with Recurrent Spontaneous Abortion Among Azerbaijani Women from Northwest Iran.

Background: Recurrent spontaneous abortion (RSA), defined as two or more succeeding abortions during 20 weeks of gestation, affects 3-5% of pregnancies. Several studies have found that most women with RSA had at least one (and sometimes two copies) of the methylenetetrahydrofolate reductase (MTHFR) C677T variant. Materials and Methods: The study involved 118 women who had two or more spontaneous abortions (SAs) as the case group and 118 women who had at least one live birth but no SA as the control group. Clinical features such as age, body mass index (BMI), medication received, family history of abortion, and thrombophilia were investigated. Real-time PCR was used for genotyping subjects for MTHFR C677T gene polymorphism. Results: Significant differences in age, BMI, and medication received characters have been shown between those in the patients' group. For the MTHFR C677T gene, the genotypes for the patients' group were 36%, 60%, and 4%, whereas the genotypes for the control group were 30%, 58%, and 12%. In addition, the C and T allelic frequencies were 59% and 41% in the healthy control group and 67% and 33% in the patients' group, respectively. A significant association was found between the TT genotype and RSA. A 3.84-fold increased risk of RSA was associated with the TT genotype (odds ratio = 3.84, confidence interval: 1.28-10.93, p-value = 0.02). Conclusions: In this study, homozygosity for the T allele was significantly lower in the RSA-affected than in healthy women, whereas heterozygosity did not vary substantially between the two groups, which was in line with other studies.

A Curious Case of Acute STEMI in a Young Patient; Things are Not Always What They Seem

BACKGROUND: Acute myocardial infarction (MI) is a rare occurrence in patients under 40 years of age without positive family history for coronary artery disease (CAD). Genetic conditions as inherited thrombophilia can lead to a hypercoagulable state, resulting in thromboembolic events and arterial thrombosis. CASE SUMMARY: We present a case of a 35-year-old male patient who presented to the emergency room with an inferior MI after a strenuous cycling exercise. An urgent coronary angiography showed thrombotic formations in the right coronary artery without atherosclerotic plaques. Plain old balloon angioplasty and thrombus aspiration were performed, which was followed by GP IIb/IIIa inhibitor infusion and unfractionated heparin for 24 h. From past medical history, the patient had COVID-19 like symptoms 20 days before the event and had his first dose of anti- COVID vaccine 2 weeks prior. After additional testing, molecular genetic analysis results revealed the patient to be heterozygous for factor V Leiden (FVL) and homozygous for methylenetetrahydrofolate reductase C677T gene mutation. The patient was discharged on direct oral anticoagulant and antiplatelet therapy. After 1-year follow-up, he had no symptoms or recurrent cardiovascular events. CONCLUSION: Inherited thrombophilia is а significant risk factor for CAD and performing genetic testing in younger patients with a cardiovascular  event and plays an important role for adequate treatment and prophylaxis from recurrent complications. The use of oral anticoagulation for prophylaxis is shown to be effective in these patients. However, further studies are needed to prove their exact role and duration of treatment.

Associations of serum 25-hydroxyvitamin D with serum folate, cobalanin, and homocysteine concentrations and methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms in healthy adults.

The aim of this study was to investigate the associations of serum 25-hydroxyvitamin D [25(OH)D] with various demographic, anthropometric, and genetic characteristics and biochemical parameters in healthy Greek adults. Demographic (age and sex), anthropometric (body mass index/BMI), and genetic (MTHFR gene polymorphisms) characteristics and biochemical parameters (serum folate, cobalamin/Cbl, and total homocysteine/tHcy concentrations), which had been recorded and measured, among others, in the framework of periodic medical examination (military personnel) or check-up (non-military personnel) of 383 healthy Greek adults (199 men and 184 women) were analyzed. Serum 25(OH)D, tHcy, folate, and Cbl levels were determined using immunoassay methods. The MTHFR C677T and A1298C gene polymorphisms were genotyped using polymerase chain reaction and reverse hybridization. Serum 25(OH)D concentrations were correlated with Cbl levels and MTHFR C677T gene polymorphism, while they had a reverse correlation with serum tHcy levels, age, and BMI. There was no significant correlation between serum 25(OH)D concentrations and sex, serum folate levels, and smoking status. Individuals with the 677TT genotype had statistically significantly lower serum 25(OH)D levels than those with the 677CC or 677CT genotype, while individuals with the 1298CC genotype had statistically significantly higher serum 25(OH)D levels than those with 1298AA or 1298AC genotype. Moreover, the reverse correlation between the serum 25(OH)D and tHcy levels was statistically significant in all six MTHFR genotypes. Serum 25(OH)D levels are associated with age, BMI, serum tHcy, and Cbl levels and MTHFR C677T gene polymorphism. The most significant finding of our study is the observed reverse correlation of serum 25(OH)D levels with serum tHcy levels. Considering that vitamin D deficiency and hyperhomocysteinemia (HHcy) are associated with an increased risk for cardiovascular diseases (CVDs), we suggest that individuals with high serum tHcy levels should be further investigated for, inter alia, their serum 25(OH)D levels.

INFLUENCE OF THE METHYLENE TETRAHYDROFOLATE REDUCTASE (MTHFR) GENE POLYMORPHISMS ON SERUM FOLATE, COBALANIN AND HOMOCYSTEINE LEVELS IN HEALTHY GREEK ADULTS

Objective: Methylene tetrahydrofolate reductase (MTHFR) is a key enzyme of homocysteine metabolism participating in the folate cycle. It is well known that hyperhomocysteinemia is associated with an increased risk for cardiovascular disease. The aim of this study was to investigate the association of MTHFR C677T and MTHFR A1298C gene polymorphisms with serum folate, cobalamin (Cbl) and homocysteine (Hcy) concentrations in healthy Greek adults. Design and method: The MTHFR C677T and A1298C gene polymorphisms were genotyped in 383 healthy Greek adults (199 men; mean age±SD: 37.3±8.2 years) using polymerase chain reaction and reverse hybridization. Serum folate, Cbl and total Hcy (tHcy) levels were determined using immunoassays methods. Results: Among the 383 individuals, 73 (19.1%) were normal (CC), 202 (52.7%) were heterozygous (CT) and 108 (28.2%) were homozygous (TT) regarding the MTHFR C677T gene polymorphism, while 263 (68.7%) were normal (AA), 105 (27.4%) were heterozygous (AC) and 15 (3.9%) were homozygous (CC) regarding the MTHFR A1298C gene polymorphism. The overall C and T allele frequency for the MTHFR C677T gene polymorphism was 45.4% and 54.6%, respectively, while the overall A and C allele frequency for the MTHFR A1298C gene polymorphism was 82.3% and 17.6%, respectively. The individuals with 677TT genotype had significantly lower serum folate and significantly higher serum tHcy levels than individuals with 677 CC or CT genotypes. On the contrary, the A1298C gene polymorphism had no significantly influence on serum folate and tHcy levels. Conclusions: Serum folate and tHcy levels are influenced by the existence of the MTHFR C677T gene polymorphism (mainly 677TT genotype). Individuals with low serum folate levels and/or high serum tHcy levels should be further investigated for a possible existence of MTHFR C677T and not A1298C gene polymorphisms, with aim to determine the suitable treatment.

Association of C677T and A1298C genetic polymorphisms in MTHFR gene with fetal growth restriction, small for gestational age and low birth weight: A meta-analysis

Impaired fetal growth has a wide range of short-term and long-term effects on physical and mental health. Fetal Growth Restriction (FGR), Small for Gestational Age (SGA) and Low Birth Weight (LBW) are three diagnoses of impaired fetal growth/size, but differences between them are not fully understood. This meta-analysis aimed to investigate the association of two genetic variants C677T and A1298C in methylenetetrahydrofolate reductase (MTHFR) gene with the risk of impaired fetal growth and then confirm this association with specific diagnosis. According to PRISMA protocols, 24 articles were included after searching the following databases: PubMed, Google Scholar, Science Direct, Web of Science, Cochrane Library and Cyber-Lenics. Meta-analysis was conducted in dominant, recessive, and allelic models of inheritance. According to our data, MTHFR C677T is associated with higher risk of impaired fetal growth and especially with FGR susceptibility (OR = 1.93, 95% CI 1.27–2.95, P = 0.002). On the other hand, MTHFR A1298C can be suggested as a risk factor of SGA (OR = 1.61, 95% CI 1.16–2.24, P = 0.005). However, it has no significant association with FGR or LBW. Our findings help to better understand MTHFR impact on fetal growth and distinguish FGR and SGA as separated cases of fetal growth abnormality.

Associations of MTHFR gene polymorphism with lipid metabolism and risk of cerebral infarction in the Northwest Han Chinese population.

Genetic variation in the methylenetetrahydrofolate reductase (MTHFR) gene may contribute to the development of cerebral infarction (CI); however, results have been inconsistent across studies with different populations, including studies of the Chinese population. The aim of this study was to analyze the effect of MTHFR gene polymorphism on serum lipid and homocysteine levels among patients with CI in the Northwest Chinese Han population. A total of 521 CI patients and 524 non-CI controls were enrolled in the study. Polymerase chain reaction and hybridization were utilized to identify MTHFR gene polymorphisms. Multivariate logistic regression analysis was used to assess the associations of MTHFR gene polymorphism with risk of CI. Frequencies of the TT genotype and the T allele were markedly higher among CI patients than among controls. After stratifying our data by sex and age, we determined that these differences in frequency of the TT genotype and the T allele were statistically significant among participants of two different age brackets and among men, but not among women (i.e., there were no statistically significant differences between female patients and female controls). CI patients and control participants with the CT or TT genotype had significantly higher homocysteine (Hcy) levels than those with the CC genotype. Among CI patients, CT/TT carriers showed significantly lower high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) levels as compared with CC carriers, but there was no significant difference for control participants. Multivariable logistic regression analysis showed that drinking; smoking; diabetes mellitus; levels of Hcy, direct bilirubin (DB), indirect bilirubin (IB), ApoA-I, and total protein (TP); and TT genotype were significant independent risk factors for CI. The results suggested that the TT genotype of the MTHFR C677T gene polymorphism, which is associated with hyperhomocysteinemia (HHcy), might be of great clinical significance in the identification of new biomarkers for CI and in the development of individualized preventive and therapeutic strategies.

Association of Methylenetetrahydrofolate Reductase (MTHFR) Gene C677T (rs1801133) polymorphism among Sudanese patients with chronic myelogenous leukemia

Association of Methylenetetrahydrofolate Reductase (MTHFR) Gene C677T (rs1801133) polymorphism among Sudanese patients with chronic myelogenous leukemia

Association of Methylenetetrahydrofolate Reductase (MTHFR) Gene C677T (rs1801133) polymorphism among Sudanese patients with chronic myelogenous leukemia

Background: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the intracellular folate metabolism which plays an important role in carcinogenesis through DNA methylation. Objectives: The current study aimed to determine the association between MTHFR C677T polymorphisms and the risks of chronic myeloid leukemia (CML). Material and methods: This are hospital based cross sectional case control study, a total of 170 Sudanese subjects were enrolled, and 75 patients with chronic myeloid leukemia and 75 age- and sex matched healthy volunteers as a control group. Genomic DNA was extracted by sodium chloride method and The SNPs genotypes were determined using polymerase chain reaction followed by restriction fragment length polymorphism method. (PCR- RFLP). Data of this study were collected using a structured interview questionnaire and analyzed by statistical package for social sciences (version 21). Results: The frequency of the CC genotype was higher in the control group compared with patients (100%,96%), while of the CT genotype was higher in the case (4%) than in control (0.0%); the TT genotype was absent in both study groups, the frequencies T and C allele were 0.02 and 0.98 in CML patient group and 0.00, 0.100 respectively in the control group. There was no clinically significant association between age (P.value= 0.3), gender (P.value= 0.4) and genotype, also there was no statistically significant association when compare case with control genotype (p. value 0.08). Conclusion: C677T MTHFR polymorphism is not associated with the risk of CML among the Sudanese population

Impact of methylene-tetrahydrofolate reductase gene C677T and A1298C polymorphisms as a risk factor for hepatitis B virus infection

Chronic hepatitis B infection caused by Hepatitis B virus (HBV), influences over two billion people worldwide despite having an effective vaccine. With a total prevalence of 4.57%, there are 3.3 million estimated HBV carriers in Türkiye. Methylene-tetrahydrofolate reductase (MTHFR) arrange folate metabolism through nucleic acid synthesis and DNA methylation. C677T (rs1801133, p.Ala222Val) and A1298C (rs1801131, p.Glu429Ala) polymorphisms of MTHFR gene have effect of reducing the activity of enzyme. We purposed to investigate the correlation between C677T and A1298C polymorphisms of MTHFR gene with HBV infection in a Turkish population. One hundred eighteen HBV-infected participants and ninety healthy controls were incorporated in this research. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was applied to discover the genotypes of MTHFR polymorphisms. We demonstrated that T allele and CT + TT genotype frequencies of C677T polymorphism were significantly increased in HBV-infected participants than healthy controls [p = 0.015, OR (95% Cl) = 1.7 (1.11–2.79) and p = 0.020, OR (95% Cl) = 1.9 (1.10–3.42), respectively). No significant associations were noted concerning the A1298C polymorphism (p > 0.05). CC-AA composite genotype was observed to be significantly elevated in healthy controls than HBV-infected participants (32.2% vs. 13.6%, p = 0.001). In addition, the frequency of T-C haplotype was found to be considerably higher in the patient group than control group (15.8% vs 11.8%, p = 0.018). In conclusion, we found that T allele of C677T polymorphism poses a risk factor for HBV infection. We also discovered a protective impact of the CC-AA composite genotype against HBV infection and a risk effect of the T-A haplotype for HBV-infection.

[Relationship between MTHFR Gene Polymorphism(C677T) and Adverse Reactions of High-Dose Methotrexate in Pediatric Patients with Acute Lymphoblastic Leukemia].

To explore the effects of methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism on the adverse reactions of high-dose methotrexate (MTX) in pediatric patients with acute lymphoblastic leukemia (ALL). A total of 69 children with ALL admitted to the department of Pediatrics of Sun Yat-sen Memorial Hospital of Sun Yat-sen University from November 2018 to October 2020 were included in this study. The clinical data of the children were collected, leukocytes were isolated from their peripheral blood, and MTHFR genotyping was performed by digital fluorescence molecular hybridization techniques. The adverse reactions and plasma drug concentration of MTX were monitored during the chemotherapy. Moreover, the effect of MTHFR gene polymorphism on MTX adverse reactions and plasma drug concentration were analyzed. Among the middle and high risk children, compared with the wildtype group (CC genotype), patients with MTHFR C677T mutations (CT+TT genotypes) had a higher risk of leukopenia (OR=2.38), neutropenia (OR=2.2), anemia (OR=1.83) and hepatoxicity (OR=1.98). However, no significant difference was found in the MTX plasma concentration between the MTHFR C677T mutantion group and the wildtype group at different timepoints (24 h, 48 h and 72 h). Multivariate analysis revealed that the plasma concentration of MTX (48 h), clinical risk level of ALL and MTHFR C677T gene polymorphism were independent factors for the adverse reactions of high-dose MTX. The MTHFR C677T mutations may be associated with myelosuppression and hepatotoxicity in children with ALL after high-dose MTX treatment.

Association of methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms with serum folate, cobalanin and homocysteine concentrations in Greek adults

Methylene tetrahydrofolate reductase (MTHFR) is a key enzyme of homocysteine metabolism participating in the folate cycle. The aim of this study was to investigate the association of MTHFR C677T and MTHFR A1298C gene polymorphisms with serum folate, cobalamin (Cbl) and homocysteine (Hcy) concentrations in healthy Greek adults. The MTHFR C677T and A1298C gene polymorphisms were genotyped in 383 healthy Greek adults (199 men and 184 women) using polymerase chain reaction and reverse hybridization. Serum folate, Cbl and total Hcy (tHcy) levels were determined using immunoassays methods. Among the 383 individuals, 73 (19.1%) were normal (CC), 202 (52.7%) were heterozygous (CT) and 108 (28.2%) were homozygous (TT) regarding the MTHFR C677T gene polymorphism, while 263 (68.7%) were normal (AA), 105 (27.4%) were heterozygous (AC) and 15 (3.9%) were homozygous (CC) regarding the MTHFR A1298C gene polymorphism. The overall C and T allele frequency for the MTHFR C677T gene polymorphism was 45.4% and 54.6%, respectively, while the overall A and C allele frequency for the MTHFR A1298C gene polymorphism was 82.3% and 17.6%, respectively. The MTHFR C677T and not the A1298C gene polymorphism had a significantly influence on serum folate and tHcy levels. The individuals with 677TT genotype had significantly lower serum folate and significantly higher serum tHcy levels than individuals with 677 CC or CT genotypes. Serum folate and tHcy levels are influenced by the existence of the MTHFR C677T gene polymorphism (mainly 677TT genotype). Individuals with low serum folate levels and/or high serum tHcy levels should be further investigated for a possible existence of MTHFR C677T and not A1298C gene polymorphisms, with aim to determine the suitable treatment.

Association of MTHFR gene C677T polymorphism with pregnancy outcome.

The two objectives of the present study were to analyze the correlation between pregnancy outcomes and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism, and to provide evidence for clinical improvement of adverse pregnancy outcomes. 1,995 cases of pregnant women were selected as objects of the study, and underwent MTHFR gene C677T polymorphism detection in the Second Affiliated Hospital of Guangxi Medical University from October 2020 to September 2021, in which 919 cases whose pregnancy outcomes could be tracked. According to the result of MTHFR gene C677T polymorphism detection, 1,995 cases of pregnant women were classified into a wild-type (CC) group, heterozygous (CT) group, or homozygous (TT) group, and the distributions of MTHFR gene C677T polymorphism in pregnant women were analyzed. In addition, according to complications, 919 cases of pregnant women whose pregnancy outcomes could be tracked were divided into the normal pregnancy group (676 cases), GDM group (146 cases), HDP group (47 cases), abnormal fetus group (13 cases), and spontaneous abortion group (37 cases), and the genotype distributions of MTHFR gene C677T in each group were analyzed. Besides, according to genotype, 919 cases of pregnant women whose pregnancy outcome could be tracked were divided into CC group (515 cases), CT group (289 cases), and TT group (115 cases), and the correlation between genotype and pregnancy outcomes, such as fetal distress, postpartum hemorrhage, premature birth, and full-term delivery, was then analyzed. For the C677T locus of MTHFR gene in the 1,995 cases of pregnant women, there are 1,162 (58.25%) cases of CC genotype, 649 (32.53%) cases of CT genotype, 184 (9.22%) cases of TT genotype. The proportion of TT genotype in GDM, HDP, abnormal fetus, and spontaneous abortion groups were respectively 19.86% (29/148), 25.53% (12/47), 46.15% (6/13), 40.54% (15/37), which were significantly higher than that in normal pregnancy group (7.84%, 53/676), and there were statistically significant differences (p < 0.05). The full-term birth rate in TT group (75.65%, 87/115) was lower than those of CC group (91.26%, 470/515) and CT group (89.27%, 258/289), and there were statistically significant differences (p < 0.05). The TT type gene mutation at the C677T site ofMTHFR gene is closely related to conditions that contribute to a decrease in the number of full-term births and increase the risk of adverse pregnancy outcomes, including GDM, HDP, spontaneous abortion, and fetal abnormalities.

The role of methylenetetrahydrofolate reductase gene polymorphisms hypercoagulable status of coronavirus disease

Abstract Background: Hypercoagulation is a hallmark in coronavirus disease (COVID-19). The activity of the enzyme methylenetetrahydrofolate reductase (MTHFR) determines homocysteine levels, and polymorphisms in the enzyme’s gene can influence the enzyme activity with a consequence of hypercoagulability in patients with COVID-19. Objectives: To investigate the association of two single nucleotide polymorphisms (SNPs) in the MTHFR gene with hypercoagulability status in COVID-19. Materials and Methods: This is a retrospective cross-sectional study, which included 90 patients diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with variable severity. Patients were classified according to D-dimer level at admission into two groups: with and without hypercoagulability. Nucleic DNA was extracted from leukocytes and gene fragments corresponding to C677T and A1298C MTHFR gene were amplified and genotyped using allele specific polymerase chain reaction. Results: Hypercoagulation was reported in 42.22% of the patients. The mutant homozygous genotype (TT) was more frequent among hyper - than normocoagulable patients (13.6% vs. 1.92%) with a significant difference (odds ratio [OR] = 9.28, 95% confidence interval [CI] = 1.02–84.78, P = 0.048). Furthermore, T allele was more common among hyper- than normocoagulable patients (28.95% vs. 13.46%) with a significant difference (OR = 2.62, 95% CI = 1.24–5.5, P = 0.012). In contrast, the SNP A1298C had no significant impact. Conclusions: The TT genotype and T allele of C677T polymorphism but not A1298C in cMTHFE gene could be considered a risk factor for the hypercoagulable status in COVID-19.

Relationship between methylenetetrahydrofolate reductase gene polymorphisms and methotrexate drug metabolism and toxicity.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, and methotrexate (MTX) is the key drug for ALL. Studies on the relationship between High-Dose methotrexate (HD-MTX) toxicity and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genes have drawn different conclusions. This study aimed to investigate the relationship between the polymorphism of MTHFR C677T and A1298C genes and the toxicity responses of MTX. The MTHFR C677T and A1298C genotypes of 271 children with ALL who received HD-MTX chemotherapy in southern China from September 2017 to June 2021 were analyzed, and the toxicity of HD-MTX was evaluated and analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0. The MTHFR C677T and A1298C gene polymorphisms were not correlated with the 48-hour MTX blood concentrations (P>0.05). Unconditional logistic regression model analysis also revealed that the risk of liver function impairment [odds ratio (OR) =1.656, 95% confidence interval (CI): 1.179-2.324, P<0.05] and mucosal damage (OR =1.508, 95% CI: 1.042-2.183, P<0.05) were 1.656 and 1.508 times higher for the heterozygous mutant (CT), and homozygous mutant (TT) mutant type than for the wild-type (CC), wild-type, respectively. The risk of neutropenia and liver function impairment were 0.498 (OR =0.498, 95% CI: 0.251-0.989, P<0.05) and 6.067 (OR =6.067, 95% CI: 1.183-31.102, P<0.05) times higher in low-risk children with CT+TT mutant genotypes than in those with CC wild genotypes, respectively. Furthermore, the risk of mucosal damage was 1.906 times higher in high-risk children with the CT+TT genotype than in those with the CC genotype (OR =1.906, 95% CI: 1.033-3.518, P<0.05). The MTHFR A1298C genotypes differed in the incidence of liver function damage and gastrointestinal toxic reactions in children with ALL. Nonetheless, no increased risk of liver function impairment nor gastrointestinal reactions in children with the heterozygous mutant (AC)+CC mutation was observed. Advancements in MTHFR genotype testing in children with ALL and the introduction of personalised treatments based on genotype results during HD-MTX chemotherapy will help to predict, prevent, and reduce the occurrence of adverse MTX-related toxic reactions.