Methylenetetrahydrofolate Reductase A1298C Research Articles

Bilateral multiple recurrent branch retinal vein occlusions secondary to hypercoagulopathy associated with multiple mutations: A rare case report

Abstract: Retinal vein occlusions (RVOs) are relatively common vascular disorders, often resulting in significant visual impairment. We present an intriguing case of a 53-year-old male with recurrent bilateral branch RVOs stemming from underlying hypercoagulopathy. This complex scenario encompassed simultaneous bilateral RVO occurrences and subsequent unilateral recurrences. Despite the absence of systemic comorbidities or conventional risk factors, genetic assessment unveiled notable heterozygous mutations involving Factor V Leiden (G1691A) and Factor II (PT G20210A), along with a homozygous methylenetetrahydrofolate reductase A1298C mutation. While routine hematological indicators remained largely unremarkable, the marked efficacy of anti-vascular endothelial growth factor (anti-VEGF) agents, particularly when administered promptly, emerged as a noteworthy therapeutic avenue. This case underscores the imperative of scrutinizing thrombotic mutations in youthful patients with recurrent RVOs, accentuating the favorable retinal response to anti-VEGF interventions and emphasizing the rewards of timely clinical intervention.

Skin disorders in women with poor obstetric history: MTHFR polymorphisms and importance of preconceptional counseling

Background This study focused on the link between skin disorders and Methylenetetrahydrofolate reductase (MTHFR) polymorphisms. Methods Study cases were taken from a pre-conceptional care program where patients with poor obstetric history were evaluated in terms of systemic disorders including skin diseases. This retrospective cohort (n = 472) consisted of 110 (23.3%) and 362 (76.7%) women with or without skin disorders, respectively. For ease of analysis, the history of skin diseases was classified into seven categories: 1) acne/rosacea/other acneiform disorders; 2) fungal disease; 3) pruritis/xerosis; 4) psoriasis vulgaris; 5) acrochordons and other benign skin growths; 6) urticaria/dermatitis; and 7) viral diseases. Results In this retrospective cohort of 472 women, we explored the impact of MTHFR A1298C and C677T polymorphisms on skin disorders. Despite similar allelic frequencies, our findings revealed a statistically significant association between the presence of MTHFR polymorphisms and skin disorders (p = 0.027). Subgroup analysis indicated significantly higher rates of MTHFR polymorphisms in patients with psoriasis vulgaris (p = 0.033) and acrochordons (p = 0.030), highlighting their potential relevance in specific skin disorder subtypes. Conclusions The increased prevalence of psoriasis and acrochordons among women with MTHFR deficiency underscores the complex relationship between genetic factors and dermatological health. Our findings emphasized the critical role of MTHFR polymorphisms not only in poor obstetric history but also as significant contributors to skin disorders. This dual association highlights the importance of comprehensive preconception counseling, especially customized for women affected by skin disorders.

Prevalence of MTHFR Polymorphisms in Patients With Hypermobile Ehlers-Danlos Syndrome and Hypermobile Spectrum Disorders in a US Hypermobility Clinic.

Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are characterized by joint hypermobility, joint subluxations and dislocations, hyperextensible skin, and chronic and progressive multiorgan comorbidities. Diagnosing hEDS and HSD is difficult because of variable phenotypes and unknown genetic etiology. In our clinic, we observed many patients with hEDS and HSD with a high serum level of unmetabolized folate, which suggests that hypermobility may be linked to methylenetetrahydrofolate reductase (MTHFR)-mediated folate metabolism. The present study aims to examine the prevalence of MTHFR polymorphisms, C677T and A1298C, among patients with hEDS and HSD. Clinical and demographic information of patients visiting our hypermobility clinic from January 2023 to July 2023 were retrospectively reviewed. Continuous variables were reported as mean ± SD and range, whereas categorical variables were reported as total count and percentage. Among 157 patients, 93% of patients were female patients, 52.2% were diagnosed with hEDS, and 47.8% were diagnosed with HSD. Interestingly, 85% of the patients had MTHFR C677T and/or A1298C polymorphisms in heterozygous or homozygous state. MTHFR 677CT/TT genotype was present in 52.9% of cases, and 49.7% of patients had 1298AC/CC genotype. In addition,14% of patients with hypermobility exhibited MTHFR 677TT genotype, 10.2% showed 1298CC genotype, and 17.2% displayed combined heterozygosity, collectively representing 41.4% hypermobile patients with two copies of MTHFR variant alleles. There is a high prevalence of MTHFR polymorphisms among patients with hypermobility, which supports the hypothesis that hypermobility may be dependent on folate status.

Interaction effects of MTHFR C677T and A1298C polymorphisms with maternal glycated haemoglobin levels on adverse birth outcomes.

The role of maternal genetic factors in the association between high glycated haemoglobin (HbA1c) levels and adverse birth outcomes remains unclear. In this study, the maternal HbA1c levels of 5108 normoglycemic pregnant women in China were measured, and A1298C and C677T polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene were genotyped. Elevated HbA1c levels during the second trimester were associated with increased risks of macrosomia, large-for-gestational age (LGA), preterm birth (PTB), and reduced gestational age (p<0.05). Pregnant women with MTHFR A1298C AA or C677T CT+TT genotypes were susceptible to adverse pregnancy outcomes related to HbA1c levels. Among pregnant women with the A1298C AA genotype, each standard deviation (SD) increase in HbA1c levels increased the risk of PTB by 1.32-times and reduced the gestational age by 0.11weeks (p<0.05). For MTHFR C677T CC+TT genotype carriers, higher HbA1c levels were associated with 1.49-, 1.24-, and 1.23-times increased risks of macrosomia, LGA, and PTB, respectively (p<0.05). A U-shaped curve for PTB risk in relation to HbA1c levels was observed among the C677T CC+TT participants, with a cut-off value of 4.58%. Among subjects with the A1298C AA genotype combined with the C677T CT+TT genotype, each SD increase in HbA1c levels was associated with 1.40 and 1.37-times increased risks of LGA and PTB, respectively. Our findings highlight the importance of glycaemic control during pregnancy and the potential impact of genetic factors on birth outcomes. However, further large-scale studies are required to confirm these findings.

Maternal methylenetetrahydrofolate reductase (MTHFR) A1298C polymorphism: implications in preventing recurrent pregnancy loss.

Maternal methylenetetrahydrofolate reductase (MTHFR) A1298C polymorphism: implications in preventing recurrent pregnancy loss.

Association of inherited thrombophilia mutations and their combinations among palestinian women with unexplained recurrent miscarriage

BackgroundInherited thrombophilia (IT) has a complex pathophysiology and is associated with recurrent miscarriage (RM) by causing placental insufficiency and inhibiting fetal development. However, thrombophilia screening in unexplained RM cases is still questionable. This study aimed to investigate the association between the common eight IT mutations and their combinations among Palestinian women with unexplained RM.MethodsThis is an unmatched case-control study with 200 women (100 unexplained RM cases, 100 controls). Eight common IT mutations namely Factor V Leiden (FVL), prothrombin gene (FII) G202120A, Methylenetetrahydrofolate Reductase (MTHFR) gene (C677T and A1298C), B-fibrinogen gene − 455G > A, FV HR2 A4070G, Plasminogen activator inhibitor 1 (PAI1) 5G/4G and Factor XIIIA (FXIIIA) V34L; were analyzed. The first five mutations were analyzed by Restriction Fragment Length Polymorphism PCR and the other three mutations were analyzed using Amplification Refractory Mutation System PCR.ResultsThe prevalence of the eight IT mutations among the control group was in the order PAI1 5G/4G (69%), MTHFR C677T (53%) and A1298C (47%), BFG − 455G > A (35%), FVL and FV HR2 (each 18%), FXIIIA V34L (16%) and FII G20210A (3%). Patients had a higher percentage of MTHFR A1298C (heterozygotes and mutant homozygote) compared to controls (p = 0.016). Frequencies of mutant alleles MTHFR A1298C (p < 0.001) and FXIIIA V34L (p = 0.009) were higher among patients compared to controls. No significant differences were observed for all other mutations or mutant alleles. Most patients (75%) and controls (75%) have 2–4 mutant alleles out of 8 mutant alleles studied, while 1% of patients and 2% of controls have zero mutant alleles. None of the combinations of the most often studied mutations (FVL, FII G20210A, MTHFR C1677T, and MTHFR A1298C) showed a significant difference between patients and controls.ConclusionsThere was a significant association between unexplained RM and the mutant alleles of MTHFR A1298C and FXIIIA V34L. No significant association was observed between unexplained RM and the combination of both mutant alleles for the mutations studied. This study is the first Palestinian report that evaluates eight inherited thrombophilia mutations and their alleles’ combinations in unexplained RM cases.

Methylenetetrahydrofolate reductase polymorphic variants C677T and A1298C in rectal cancer in Slavic population: significance for cancer risk and response to chemoradiotherapy.

Background: Methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms (SNPs) have been suggested as risk, prognostic, and predictive factors for colorectal cancer in various populations, but have not been validated so far. The aim of this study was to examine the association of MTHFR C677T (rs1801133) and A1298C (rs1801131) single nucleotide polymorphisms with the risk of rectal cancer as well as the response to neoadjuvant chemoradiotherapy (nCRT) based on 5-Fluorouracil (5-FU)/leucovorin (LV) in the locally advanced setting. Patients and methods: This case-control study included 119 healthy controls and 97 patients with locally advanced rectal cancer (LARC). For MTHFR genotyping, restriction fragment length polymorphism analysis (PCR-RFLP) was employed. Results: In silico analysis highlighted that SNPs C677T and A1298T correlate with MTHFR gene expression, and that gene expression profile correlates with cancer risk and stage. Using dominant and recessive models, it was found that the MTHFR 677CC vs. 677CT+677TT have increased risk of cancer development (odds ratio (OR): 2.27; 95% confidence interval (CI): 1.30-3.95, p = 0.002) as well as 677CC+677CT compared to 677TT (OR: 4.18, 95% CI: 1.16-14.99, p = 0.014). MTHFR 1298AA also shown increased risk for cancer development compared to 1298AC+1298CC (OR:2.0, 95% CI: 1.20-3.59, p = 0.035) Statistical analysis of combined genotypes highlighted the protective role of CT/AC combined genotype (OR: 3.15 95% CI: 1.576-6.279, p = 0.002) while the CC/AA genotype showed an increased risk for rectal cancer development (OR: 2.499, 95% CI: 1.246-5.081, p = 0.016) The carriers of the 677C/1298A haplotype had the highest risk for developing rectal cancer (OR: 1.74; 95% CI: 1.198-2.530, p = 0.002) while the 677T/1298C haplotype seems to provide a protective effect. (OR: 0.44; 95%CI 0.248-0.795, p = 0.003). No significant association with response to chemoradiotherapy was found. Conclusion: Our data point to MTHFR 667C allele and 1298A alleles as low-penetrance risk factors for rectal cancer in our population. To the best of our knowledge, this is the first study of this type performed on the Slavic population in the Western Balkan, as various population-based factors might also be significant our findings can be used for future meta-analyses and the construction of genetic cancer risk prediction panels.

The relevance of prothrombotic genetic variants in women who experienced pregnancy loss or embryo implantation failure: A retrospective analysis of 1922 cases.

The aim of our study was that to assess the allelic and genotype frequencies of nine prothrombotic gene variants in patients with a history of pregnancy loss and recurrent pregnancy loss (RPL). Women who underwent assisted reproductive technology (ART) with ongoing pregnancy and those with recurrent implantation failure (RIF) were also included. Nine prothrombotic gene variants were evaluated: factor V Leiden (FVL), factor V, H1299R variant (FVR2), factor II (FII) G20210A, methylene-tetrahydrofolate reductase (MTHFR) C677T and A1298C, beta-fibrinogen -455G>A, factor XIII (FXIII) V34L, human platelet antigen-1 (HPA-1) L33P variants, and plasminogen activator inhibitor-1 (PAI-1) 4G/5G. The following study groups were assessed: (1) women who experienced one (n = 334) or two (n = 264) episodes of pregnancy loss; (2) 468 women who experienced RPL; (3) 214 women who underwent ART followed by ongoing pregnancies; and (4) 282 women who experienced RIF after ART, that is, three or more consecutive implantation failures following high-quality embryo transfers to the uterus with an appropriate endometrium. As control group, 430 subjects from the general population were enrolled. FVL, the -455G>A variant of beta-fibrinogen, and PAI-1 4G were associated with a higher risk of developing RPL compared with the general population. Furthermore, FVL, FVR2, FII G20210A and MTHFR C677T conferred a significantly higher risk of RIF in women who performed ART compared with the general population. No statistical differences between the general population and other study groups were observed. Specific prothrombotic genetic variants are more frequently expressed in women with RPL and RIF, supporting their role in the development of polimicrothrombosis and impairing the invasion during embryo implantation.

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 of epistatic effects of MTHFR, ACE, APOB, and APOE gene polymorphisms with the risk of myocardial infarction and unstable angina in Egyptian patients

Despite remarkable discoveries in the genetic susceptibility of coronary artery disease (CAD), a large part of heritability awaits identification. Epistasis or gene‐gene interaction has a profound influence on CAD and might contribute to its missed genetic variability; however, this impact was largely unexplored. Here, we appraised the associations of gene-gene interactions and haplotypes of five polymorphisms, namely methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, angiotensin converting enzyme (ACE) insertion/deletion (I/D), apolipoprotein B (APOB) R3500Q, and apolipoprotein E (APOE) ε4 with the risk of myocardial infarction (MI) and unstable angina (UA). Gene-environment interactions with traditional risk factors and clinical data were also scrutinized. This study recruited 100 MI, 50 UA patients, and 100 apparently healthy controls. Logistic regression models were employed in association analyses. We remarked that the single locus effect of individual polymorphisms was relatively weak; however, a magnified effect of their combination via gene-gene interaction may predict MI risk after adjustment for multiple comparisons. Only MTHFR C677T, ACE I/D, and APOB R5300Q were associated with the risk of UA, and the ACE I/D-R3500Q interaction posed a decreased UA risk. APOB R3500Q was in strong linkage disequilibrium with MTHFR C677T, ACE I/D, and APE ε4 polymorphisms. The TCDGε3, CADGε4, and TADGε4-C677T-A1298C-ACE I/D-R3500Q-APOE haplotypes were associated with escalating MI risk, while the CDG or CIG-C677T-ACE I/D-R3500Q haplotype was highly protective against UA risk compared to controls. Interestingly, the CADGε4 and CAIGε3 haplotypes were strongly associated with the presence of diabetes and hypertension, respectively in MI patients; both haplotypes stratified patients according to the ECHO results. In UA, the CDG haplotype was negatively associated with the presence of diabetes or dilated heart. Conclusively, our results advocate that a stronger combined effect of polymorphisms in MTHFR, ACE, APOB, and APOE genes via gene-gene and gene-environment interactions might help in risk stratification of MI and UA patients.

Association Between MTHFR Gene Polymorphism (A1298c) C&gt;A and Sensitivity to Cervical Cancer: A Meta-Analysis

We have investigated the association between methylenetetrahydrofolate reductase A1298C polymorphism and cervical cancer. A comprehensive search was conducted in Wanfang, China HowNet and PubMed databases to retrieve Chinese and English literature from the construction of the database to December 2019. Stata software was utilized to conduct the analysis of the five genetic models, while the odds ratio and 95% confidence interval were employed to assess the correlation. 12 pertinent publications were included with 3839 subjects (1546 patients and 2293 healthy control). There were no significant associations between A1298C and cervical cancer risk under recessive model, dominant model, allele model, co-dominant model. In the sub-analysis by ethnic groups, a significant association between A1298C and cervical cancer risk under recessive model in Asia. It is suggested a potential association between methylenetetrahydrofolate reductase gene polymorphism A1298C and an elevated susceptibility to cervical cancer in the Asian population, specifically under the recessive model.

MTHFR C677T and A1298C polymorphism’s effect on risk of colorectal cancer in Lynch syndrome

Lynch syndrome (LS) is characterised by an increased risk of developing colorectal cancer (CRC) and other extracolonic epithelial cancers. It is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes or the EPCAM gene, leading to a less functional DNA MMR system. Individuals diagnosed with LS (LS individuals) have a 10–80% lifetime risk of developing cancer. However, there is considerable variability in the age of cancer onset, which cannot be attributed to the specific MMR gene or variant alone. It is speculated that multiple genetic and environmental factors contribute to this variability, including two single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene: C677T (rs1801133) and A1298C (rs1801131). By decreasing MTHFR activity, these SNPs theoretically reduce the silencing of DNA repair genes and increase the availability of nucleotides for DNA synthesis and repair, thereby protecting against early-onset cancer in LS. We investigated the effect of these SNPs on LS disease expression in 2,723 LS individuals from Australia, Poland, Germany, Norway and Spain. The association between age at cancer onset and SNP genotype (risk of cancer) was estimated using Cox regression adjusted for gender, country and affected MMR gene. For A1298C (rs1801131), both the AC and CC genotypes were significantly associated with a reduced risk of developing CRC compared to the AA genotype, but no association was seen for C677T (rs1801133). However, an aggregated effect of protective alleles was seen when combining the alleles from the two SNPs, especially for LS individuals carrying 1 and 2 alleles. For individuals with germline pathogenic variants in MLH1, the CC genotype of A1298C was estimated to reduce the risk of CRC significantly by 39% (HR = 0.61, 95% CI 0.42, 0.89, p = 0.011), while for individuals with pathogenic germline MSH2 variants, the AC genotype (compared to AA) was estimated to reduce the risk of CRC by 26% (HR = 0.66, 95% CI 0.53, 0.83, p = 0.01). In comparison, no association was observed for C677T (rs1801133). In conclusion, our study suggests that combining the MMR gene information with the MTHFR genotype, including the aggregated effect of protective alleles, could be useful in developing an algorithm that estimates the risk of CRC in LS individuals.

Evaluation of acquired and hereditary risk factors for the development of thromboembolism in patients with systemic lupus erythematosus.

Although the contribution of antiphospholipid antibodies (aPL) to thrombolembolism in systemic lupus erythematosus (SLE) is well known, there is not enough data on the contribution of various hereditary thrombophilic factors. In this study, we aimed to determine acquired and hereditary thrombophilic factors in adult patients with SLE. A total of 93 SLE patients (87 women and 6 men) were included. Data on clinical, demographic and laboratory characteristics, and disease activity scores (SLEDAI) of the patients were evaluated. The patients were analyzed with a screen, including lupus anticoagulant, anticardiolipin antibodies (aCL), antithrombin III, protein C, protein S, and homocysteine levels; factor V Leiden ( FVL ), methylenetetrahydrofolate reductase ( MTHFR ) and prothrombin G20210A gene mutations. A total of 23 thromboembolic events were reported in 17 (18.3%) of the patients. The frequency of pregnancy complications and SLEDAI scores were significantly higher in SLE patients who had a thromboembolism event ( P  < 0.05). Thromboembolism was detected in 12 (32.4%) of 37 patients with positive aPL antibody and 5 (8.9%) of 56 patients with negative aPL antibody ( P  = 0.006). In addition, thromboembolism developed in 11 (32.3%) of 34 lupus anticoagulant-positive patients and 6 (10.1%) of 59 lupus anticoagulant-negative patients ( P  = 0.012). Moreover, protein C levels were significantly lower in patients who developed thromboembolism ( P  < 0.05). Patients with and without thromboembolism were similar in terms of genetic thrombophilia factors ( MTHFR A1298C, MTHFR C677T, FVL and Prothrombin G20210A ) ( P  > 0.05). In conclusion, in the current study, some acquired (aPL, lupus anticoagulant and cCL IGG) and hereditary (protein C deficiency) thrombophilic factors were shown to be associated with the development of thrombosis in SLE patients. However, the effect of other hereditary factors on the development of thromboembolism could not be demonstrated. According to the data of this study, genetic screening seems inappropriate in terms of the risk of thromboembolism in patients with SLE.

Türkiye'nin Doğu Anadolu Bölgesi'nde Venöz Tromboembolizm olan Hastalarda Trombofilik Gen Mutasyonlarının Sıklığının Araştırılması

Objectives: Polymorphisms in the thrombophilia genes such as Factor V Leiden (FVL), Prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR) cause genetic predisposition to thrombophilia. The regional incidence of these polymorphisms varies. The aim of our study is to evaluate the regional frequency of the most common single nucleotide polymorphisms of these thrombophilia genes.&#x0D; Methods: In this retrospective study, patients diagnosed with VTE in our center were included in the study. The presence of FVL, Prothrombin G20210A, MTHFR C677T, MTHFR A1298C, plasminogen activator inhibitor (PAI)-1, β-Fibrinogen, Factor XIIIA (V34L) and Glycoprotein IIIA (L33P) were investigated in blood samples obtained from the patients, and the association of genotype disorders was also evaluated.&#x0D; Results: Eight genotypes were analyzed in 2000 patients whose thrombophilia panel was studied in our clinic. The frequency of heterozygosity for the Factor II G20210A polymorphisms was 4,6%, the homozygosity for the Factor V Leiden polymorphism was 0,4%, for MTHFR C677T 7,6% , for MTHFR A1298C 48,1% and 15,7% , for PAI-1 38,8% and 13% , for β-Fibrinogen 30,3% and 4%, for Factor XIIIA (V34L) 23,3% and 2,4% and for Glycoprotein IIIA (L33P) 17,7% and 1,5% respectively.&#x0D; Conclusions: Factor V Leiden and Factor II (Prothrombin) G20210A mutations were found at a higher rate in our region compared to other regions in the west.

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.

No association between MTHFR gene C677T/A1298C polymorphisms, serum folate, vitamin B12, homocysteine levels, and prostate cancer in an Algerian population.

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate and homocysteine metabolism, which are necessary for DNA methylation and nucleotide synthesis. Genetic polymorphisms that reduce MTHFR activity have been linked to several diseases, including prostate cancer. In this study, we aimed to investigate whether MTHFR polymorphisms, along with serum levels of folate, vitamin B12, and homocysteine, are associated with prostate cancer risk in the Algerian population. A total of 106 Algerian men with newly diagnosed prostate cancer and 125 healthy controls were included in this case-control study. The MTHFR C677T and A1298C polymorphisms were analyzed using PCR/RFLP and Real-Time PCR TaqMan® assays, respectively. Serum levels of folate, total homocysteine, and vitamin B12 were measured using an automatic biochemistry analyzer. We found no significant differences in the genotype frequency of A1298C and C677T between prostate cancer patients and controls. Moreover, serum levels of folate, total homocysteine, and vitamin B12 were not significantly associated with prostate cancer risk (p > 0.05). However, age and family history were identified as significant risk factors (OR = 1.178, p = 0.00 and OR = 10.03, p = 0.007, respectively). Our study suggests that MTHFR C677T and A1298C, as well as serum levels of folate, total homocysteine, and vitamin B12, are not associated with prostate cancer risk in the Algerian population. However, age and family history are significant risk factors. Further studies with a larger sample size are required to confirm these findings.

MTHFR and MTRR Genetic Polymorphism of Methotrexate Therapy Outcomes in Early Rheumatoid Arthritis.

Methotrexate (MTX) is used as an anchor drug for the treatment of rheumatoid arthritis (RA) and there may be differences in drug action between genotypes. The purpose of this study was to investigate the relationship between clinical efficacy response and disease activity of MTX monotherapy with methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms. In the study, a population of 32 patients in East China with early RA fulfilling the diagnostic standards of the American College of Rheumatology (ACR) were enrolled, all of them received MTX monotherapy. Genotyping of patients MTHFR C677T and A1298C, MTRR A66G using tetra-primer ARMS-PCR method and sanger sequencing to verify its accuracy. The distribution of three polymorphic genotypes that were studied is in accordance with the Hardy-Weinberg genetic equilibrium. The patient pathology variables smoke (OR = 0.088, P = 0.037), drink alcohol (OR = 0.039, P = 0.016) and males (OR = 0.088, P = 0.037) were significantly associated with non-response to MTX. Genotype, allele distribution and genetic statistical models were not found to be related to MTX treatment response and disease activity in both the response groups and non-response groups. Our findings suggest that the MTHFR C677T, MTHFR A1298C and MTRR A66G polymorphisms may not predict MTX clinical treatment response and disease activity in patients with early RA. The study revealed that smoke, alcohol, and males were possible influential factors for MTX non-response.

Maternal pre-pregnancy BMI, MTHFR polymorphisms, and the risk of adverse pregnancy outcomes in pregnant women from South China: a retrospective cohort study

BackgroundIncreasing evidence suggests an association between maternal pre-pregnancy body mass index (pre-BMI) and adverse pregnancy outcomes. However, the effects of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on these relationships require further investigation. This study aimed to investigate whether the relationship between pre-BMI and the risk of adverse pregnancy outcomes was influenced by MTHFR gene polymorphisms.MethodsA total of 5614 mother-fetus pairs were included in the study. The odds ratios (OR) of adverse pregnancy complications, including gestational diabetes mellitus (GDM), gestational hypertension (GHT), cesarean delivery (CS), and premature rupture of membranes (PROM), were estimated using adjusted logistic regression models and subgroup analysis.ResultsPregnant women with higher pre-BMI values were positively related to the risk of GDM, GHT, and CS. In the subgroup analysis, underweight BMI was associated with a decreased risk of CS and GDM in pregnant women with the MTHFR A1298C AA or C677T CC genotype, while overweight/obese BMI was associated with an increased risk of GDM and CS in different MTHFR variants. Moreover, pregnant women with MTHFR A1298C AC + CC or C667T CC were found to have an increased risk of GHT in the MTHFR A1298C AA or C667T CT + TT genotype. A remarkable association was observed between the obesity group with MTHFR A1298C AC + CC (OR = 6.49, CI: 2.67–15.79) and the overweight group with the C667T CC genotype (OR = 4.72, CI: 2.13–10.45).ConclusionsMTHFR gene polymorphisms exert a modifying effect on the association between maternal pre-BMI and the risk of GHT, CS, and GDM. Pregnant women with a high pre-BMI with specific MTHFR genotypes should be considered for GHT development.