MTHFR Polymorphisms Research Articles

Association between gene polymorphism of folate metabolism and recurrent spontaneous abortion in Asia

To evaluate the association between gene polymorphisms of MTHFR (C677T, A1298C) and MTRR (A66G), and the recurrent spontaneous abortion (RSA) risk in Asia.Related case-control studies were collected, selected, and screened. A meta-analysis was conducted by Stata 12.0 software to assess the association between polymorphisms of target genes and RSA.Altogether 30 studies examining the relationship between genetic polymorphism of folate metabolism and RSA risk were included, among which 20 studies were related to MTHFR C677T, 11 to MTHFR A1298C and 6 to MTRR A66G. The studies suggested that MTHFR C677T polymorphism was closely connected with RSA risk under all models (P < .05). Furthermore according to the subgroup analysis of ethnicity, the correlation between C677T polymorphism and RSA was stronger in north of China when compared with south of China and other Asian countries (P > . 05). For MTHFR A1298C, it was closely related to RSA risk in all gene models except for (AC vs AA) (P < .05). However, when it comes to MTRR A66G, there was no significant correlation between gene A66G polymorphism and RSA risk except for the additive gene model (G vs A) (P < .05).The present evidence shows that the correlation between gene polymorphisms and RSA risk can be found in MTHFR C677T, A1298C (except for heterozygote model) and MTRR A66G (only in additive genotypes), and the detection of the correlated gene polymorphisms mentioned above is of certain guiding significance for preventing RSA and screening high-risk groups.

Influence of BDNF and MTHFR polymorphisms on hippocampal volume in first-episode psychosis

BackgroundThe BDNF and MTHFR genes are independently linked to the pathogenesis of schizophrenia and its neuroimaging correlates. The aim of this study was to explore, for the first time, the individual and interactional effects of the Val66Met and C677T polymorphisms on hippocampal atrophy in first-episode psychosis (FEP). MethodMulti-site case-control study based on clinical, genetic (rs 6265, rs 1801133) and structural magnetic resonance imaging data from 98 non-affective FEP patients and 117 matched healthy controls (HC). Hippocampal volume was estimated using FreeSurfer software and this volume was compared between diagnostic (FEP vs HC) and genotype (Val66Met, C677T) groups. The BDNF Val66Met x MTHFR C677T effect on hippocampal volume was further evaluated through stratified analyses. ResultsAfter applying Bonferroni correction, diagnosis showed a significant effect for adjusted left and right hippocampal volume (FEP < HC). Stratified analyses showed that the interactive effect contributed to adjusted hippocampal size in both the HC (left and right hippocampus) and FEP groups (right hippocampus); among BDNF Met carriers, those with the CT-TT genotype exhibited decreased hippocampal volume compared to individuals with the homozygous normal CC genotype. ConclusionsOur results provide preliminary evidence indicating that the Val66Met x C677T interaction may be a potential genetic risk factor for reduced hippocampal size in both healthy controls and in patients with FEP. Further research in independent samples including different ethnic groups is warranted to confirm this new finding.

MTHFR C677T polymorphism not associated with meningiomas: Study of an interethnic Brazilian population, and meta-analysis

BackgroundWe evaluated the association between MTHFR C677T polymorphism and the risk for meningioma in an interethnic population in Brazil, then conducted a meta-analysis if MTHFR C677T polymorphism could contribute to the risk of meningioma. Materials and methodsTwenty-three patients with meningioma and 96 control individuals were genotyped for the MTHFR C677T polymorphism using PCR and direct sequencing. Electronic databases were searched for eligible case-control studies. ORs with 95% CIs were used to assess the strength of the association between MTHFR C677T polymorphism and meningioma. ResultsThe genotypes and alleles were not significantly different between the patient and control groups of the Pará population. Our meta-analysis included a total of 1928 cases and 2292 controls. We found no association between the MTHFR C677T polymorphism and the risk of meningioma under five tested genetic models. ConclusionMTHFR C677T polymorphism was not associated with meningioma risk in our study. Studies with emphasis on ethnicity are relevant to have a better picture of MTHFR polymorphism association with some cancers.

The Impact of MTHFR 1298 A\u2009>\u2009C and 677 C\u2009>\u2009T Gene Polymorphisms as Susceptibility Risk Factors in Cervical Intraepithelial Neoplasia Related to HPV and Sexually Transmitted Infections

BackgroundHPV genotypes are the most common etiological factor for genital neoplasia. It would appear that sexually transmitted infections accompanied with HPV genotypes might have synergistic interactions in cancer progression. The genetic polymorphisms are involved in metabolizing carcinogens which may contribute to the susceptibility of developing genital cancers by less efficient or overly down metabolic pathways and cell signaling. MTHFR polymorphisms are related to several metabolic disorders and human cancers. We investigated the contribution of MTHFR 1298 and MTHFR 677 polymorphisms as potential risk factors for outcomes with HPV genotypes and STIs in Iranian population.Materials and MethodsAs a case–control study, MTHFR A1298C and C677T were assessed for SNPs analysis using a PCR–RFLP assay in 50 cervical intraepithelial neoplasia (CIN) cases, 98 HPV-positive subjects and 47 non-cancerous/non-HPV patients as healthy controls.ResultsFinding suggested a significant association between the MTHFR 1298 CC polymorphisms (OR = 3.5, 95% CI = 1.13–10.82, P ≤ 0.05) in women with CIN as compared to non-cancerous/non-HPV subjects. There was not a significant difference of MTHFR 677 between outcomes.DiscussionIt would seem MTHFR 1298 CC is more likely to be a potential risk factor for HPV–cervical cancer progression. Consequences support further attempts to understand the clinical manifestations of neoplasia related to genital infections and gene mutations.

Increased homocysteine expression associated with genetic changes in the folate pathway as a key determinant of preeclampsia: A prospective study from lower Assam, India

Lacunae exist in the scientific understanding of preeclampsia (PE) pathogenesis, which is a global issue and a clinical challenge during pregnancy and contributes to both maternal and fetal morbidity and mortality. We aim to understand the significance of homocysteine levels and folate pathway parameters in PE pathogenesis involving pregnancy cases from lower Assam, India. PE cases {N = 145, mild-PE (n = 108), severe-PE (n = 37)} and 192 normal full-term delivery cases were evaluated for Hcy expression and Vitamin B12 levels and evaluated for association with MTHFR and TYMS polymorphisms in PE pathogenesis. Hcy level was significantly higher in PE cases with negative pregnancy outcomes (p = 0.003) and was higher in PE-preterm delivery compared to PE-term delivery cases (p = 0.301). The VitaminB12 levels were not associated with higher tHcy concentration. Distribution of MTHFRC677T variant genotype was significantly higher in severe-PE cases compared to mild-PE cases (p = 0.050) and was associated with an increased risk of severe PE. The combined variant genotype of MTHFR and TYMSdel6 polymorphism resulted in significant increase (p = 0.014) in the risk of severe-PE compared to mild-PE. Within the PE delivery group, the combined variant genotypes showed association with higher homocysteine levels both in live birth cases as well in the PE cases with negative pregnancy outcomes. Increased homocysteine levels were associated with combined variant genotypes and were consistent in both term and preterm delivery in PE cases. The study points out the prognostic significance of MTHFR C677T, TYMS 1494del6 genotype and tHcy levels as a risk factor for PE, negative pregnancy outcome and preterm delivery.

Analysis of association between FGB, MTHFR, MTR and MTRR genes polymorphisms and ischemic and hemorrhagic stroke

The genetic component is a leading factor of stroke manifestation. Contribution of single nucleotide polymorphisms or combined genotypes to disease development has population differences. Special attention should be paid to genetic features in different types of strokes among the Ukrainian population. The aim of the study was to estimate the association of polymorphisms between FGB, MTHFR, MTR, MTRR genes or gene-gene interaction and a risk of atherotrombotic ischemic stroke and intracranial hemorrhagic stroke among Ukrainians. Materials and methods. 102 patients with atherotrombotic ischemic stroke, 56 patients with intracranial hemorrhagic stroke and 102 healthy control subjects were included in the study. The control group comprised peoples without cardiovascular diseases, family history of stroke and with normal lipid profile values. The mean age was 53.4 ± 9.1 years for stroke patients and 54.5 ± 8.2 years for the control group. Single nucleotide polymorphisms С677T (rs1801133) MTHFR gene, A66G (rs1801394) MTRR gene, A2756G (rs 1805087) MTR gene, C-148T (rs 1800787) FGB gene were detected by polymerase chain reaction (PCR) followed by restriction of amplificated fragments and polymorphism A1298C (rs1801131) MTHFR gene was determined by allele specific PCR method. Results . The association between 1298СС genotype MTHFR gene (OR = 3.457, 95 % CI:1.053–11.357) and -148СТ genotype FGB gene (OR = 2.276, 95 % CI: 1.248–4.152) and a risk of atherotrombotic ischemic stroke was revealed. A risk of intracranial hemorrhagic stroke was associated with 66AG (OR = 2.643, 95 % CI: 1.059–6.593) and 66GG (OR = 4.826, 95 % CI: 1.858–12.535) genotypes of MTRR gene. Synergistic effect was shown for polymorphic loci of FGB/С-148Т and MTRR / A66G in atherotrombotic ischemic stroke development as well as independent effect of MTRR/A66G for intracranial hemorrhagic stroke. Conclusions. There are some differences in the genetic components of different types of acute stroke in Ukrainians that should be taken into account when initiating therapy or preventative measures.

Association of ESR1 (rs2234693 and rs9340799), CETP (rs708272), MTHFR (rs1801133 and rs2274976) and MS (rs185087) polymorphisms with Coronary Artery Disease (CAD)

BackgroundCoronary artery disease (CAD) is a complex disease resulting from the cumulative and interactive effects of large number of genes along with environmental exposure. Therefore, the present study was envisaged as an effort to study the association of candidate genes ESR1 (rs2234693 and rs9340799), CETP (rs708272), MTHFR (rs1801133 and rs2274976) and MS (rs185087) polymorphisms with the risk of CAD, targeting the populations of Jammu (JandK).MethodA total of 400 confirmed CAD patients and 400 healthy controls were enrolled for the present study. Genotyping was done by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP).ResultsESR1 gene (rs9340799) polymorphism was found to be associated with CAD in all the genetic models. The haplotype analysis of ESR1 (rs2234693 and rs9340799) gene revealed that C-G haplotype was conferring approximately 5-fold risk and T-A haplotype was adding 1.4-fold risk towards the disease. ‘T’ allele of MTHFR rs1801133 SNP was observed to be responsible for development of CAD in our study population (p < 0.0001). In case of MTHFR (rs1801133 and rs2274976) gene, the haplotype T-G was observed to confer 4.7-fold risk towards CAD whereas haplotype C-G provided nearly a 1.7 fold protection towards development of CAD. For MS gene, rs185087 was also found to be associated with CAD in a co-dominant (p = 0.003 and p = 0.03), dominant (p = 0.001) and allelic models (p = 0.001). The gene-gene interaction revealed strong epistasis between single nucleotide polymorphisms (SNPs), ESR1 rs9340799 and MTHFR rs2274976. Furthermore, the dendrogram for gene-environment dataset indicated moderately synergistic interaction between CETP rs708272 and physical inactivity.ConclusionIn the study under reference, a significant association of ESR1-XbaI (rs9340799), MTHFR C677T (rs1801133) and MS A2756G (rs185087) gene polymorphisms with the susceptibility of CAD in the population of Jammu region (JandK) has been observed.

Gene polymorphism of methylentetrahydrofolate reductase C 677T in ischemic stroke at young age

Number of young people with ischemic stroke increases at the present. One of independent risk factors of stroke is hyperhomocysteinemia, wich can be caused by genetic disorders. Objective: to analyze frequency of gene polymorphism of methylentetrahydrofolate reductase C 677T and level of homocysteine among patients with stroke and people without one. Materials and methods. Data of 141 young patients with ischemic stroke, including 30 people with atherothrombotic stroke, 35 with cardioembolic, 36 with lacunar and 40 ones with cryptogenic stroke were analyzed. The control group included 40 young patients without stroke. Results. The frequency of polymorphism MTHFR C 677T (OR = 6,7; 95 % CI: 1,20–37,45: р = 0,027), allel T (OR = 2,29; 95 % CI: 1,10–4,74; р = 0,028) and the level of homocysteine are higher among stroke patients.

Genotyping 5,10-methylenetetrahydrofolate reductase for patients with coronary artery disease in Southern Taiwan

Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease (CAD). Individuals with homozygous MTHFR (5,10-Methylenetetrahydrofolate reductase) mutation have significantly elevated plasma homocysteine levels. Two common mutations in MTHFR (MTHFR 677C→T and MTHFR 1298A→C) may represent an important genetic risk factor in vascular disease. The aim of this research was to investigate these two point mutations of MTHFR for CAD patients and non-CAD controls in Southern Taiwan by PCR-restriction fragment length polymorphism assay. We found that the distribution of the homozygous mutation for MTHFR677 was higher in 54 CAD patients than in 55 non-CAD subjects (11.1% versus 3.6%, P = 0.275). On the other hand, the frequency of MTHFR 1298CC in CAD patients was similar to that of control subjects (P = 1.000). This may suggest there is a trend toward an increased risk of coronary heart disease for individuals that have a 677TT genotype in the Taiwanese population. Finally, the frequency of homozygosity for the two MTHFR common mutations was still low in CAD cases. There may not be an appreciable association of MTHFR mutation to cardiovascular disease in Taiwan. Perhaps a further study including assessment of plasma concentrations of homocysteine, folate and vitamin B12 would be needed to better clarify the relationship between MTHFR polymorphisms and the occurrence of vascular disease.

Significance of gene polymorphysm in development of colorectal cancer

Aim. To determine the significance of polymorphism of MTHFR (Ala222Val), XPD (Lis751Gln), XRCC1 (Arg194Trp), XRCC1 (Arg399Gln), XRCC1 (Arg208His), APE1 (Asp148Glu), hOGG1 (ser326Ces), P53 (Pro47Ser), VEGF (C654G), EGFR(A2073T), TNF(G308A), CHEK2 (Ile157Thr), MMP1 (1607 1G2G), TIMP1(C53CT) genes in development of colorectal cancer.&#x0D; Materials and Methods. 106 Cases of colorectal cancer in patients who were on treatment in Ryazan Clinical Oncological Dispensary (Ryazan) were analyzed. Genotyping in all patients was performed using the method of isolation of DNA from leukocytes of venous blood with subsequent polymerase chain reaction (PCR) with electrophoretic detection of the result.&#x0D; Results. No interrelation between the age of patients and polymorphism of any studied gene was recorded at the moment of verification of the diagnosis (р0.05). Statistically significant relationship was identified between polymorphism of TNF (G308A) gene and the stage of cancer: its homozygous major genotype G/G more commonly occurred in the group of patients with III-IV stage (р=0.047). In the presence of allele of G/G TNF (G308A) gene together with homozygous mutant allele of MMP1 (1607 1G/2G) gene, a direct relationship with increase in the number of patients diagnosed with III-IV stage was noted. This combination of two polymorphisms showed a statistically significant difference in the studied groups (р=0.025). In 8 out of 10 patients with IV stage, the presence of G/G polymorphism in VEGF (C654G) gene was noted. This mutant homozygous variant was much more rare in patents with I (37.5%), II (40%) or III stages (37.5%) (р=0.0147).&#x0D; Conclusions. The studied genes do not influence the age of manifestation of colorectal cancer and occur at the same frequency in patients of both genders irrespective of the age group. Localization and the extent of differentiation of the tumor do not depend on polymorphism of the studied genes either. The presence of G/A polymorphism of TNF (G308A) gene should be considered a favorable criterion associated with lower aggressiveness of the tumor (р0.05), whereas identification of the major G/G genotype especially in combination with homozygous mutant allele of MMP1 (1607 1G/2G) gene is an unfavorable factor (р0.05). The presence of G/G mutant genotype of VEGF (C654G) gene may directly correlate with rapid progression of tumor and with active metastatic spreading (р0.05).

Pregnancy outcomes in patients with MTHFR gene polymorphism: A case series

Aim: Based on the literature, MTHFR polymorphism is common among the general population and is controversial in terms of treatment, as it is poorly associated with pregnancy complications. In this study, we aimed to investigate the relationship between treatment and pregnancy outcomes in patients with MTHFR polymorphism.Methods: The data of 48 patients who were diagnosed with MTHFR C677T and A1298C polymorphism between June 2012 and April 2020 and followed up during their pregnancy were reviewed retrospectively. Demographic and clinical features of patients, pregnancy history, diagnosis, and perinatal complications were examined. Pre- and post-treatment clinical features of the patients were compared.Results: Comparison of pre- and post-treatment pregnancy data of the patients revealed that live birth rates were significantly higher (pre-treatment: 9.4% post-treatment: 68.7%, P=0.001) and abortion rates were significantly lower after treatment (pre-treatment: 81.2%, post-treatment: 32.1%, P=0.001). Pregnancy complications were observed in 9 (18.3%) patients. It was observed that among patients with MTHFR gene mutation, live birth rates increased by 24.12-fold and by 3.76-fold for each year of decrease in the age of conception following treatment. Conclusion: In pregnant women with MTHFR polymorphism, methionine-poor diet and medical treatment had a positive effect on pregnancy outcomes. It was also observed that among those with MTHFR gene polymorphism, young patients with MTHFR A1298C heterozygotes had the best treatment results.

Low folate intake and serum levels are associated with higher body mass index and abdominal fat accumulation: a case control study

BackgroundThe link between folate metabolism and obesity has recently been underlined, suggesting that folate deficiency may lead to body weight gain and adiposity. We thus wished to determine whether the inefficiency in folate metabolism caused by genetic variation in the MTHFR and DHFR genes in folate metabolism, or inadequate folate intake, is associated with obesity.MethodsA case–control study including 421 healthy participants (aged 20–40) was performed in Poznań, Poland. The cases were 213 subjects with BMI > 25 kg/m2, while the controls were 208 subjects with BMI < 25 kg/m2. Genotyping of rs70991108 (DHFR) and rs1801133 (MTHFR) was performed using TaqMan probes. Serum folate concentrations were measured using an enzyme-linked immunosorbent assay and homocysteine was assessed with high performance liquid chromatography.ResultsSubjects with overweight and obesity had 12% lower folate intake (p < 0.05) and 8.5% lower folate serum concentrations (p < 0.01) than the controls. Serum folate concentrations and folate intake were inversely associated with body fat percentage (p < 0.05) and waist circumference (p < 0.05 and p < 0.001, respectively). Serum folate concentration, though not folate intake, was negatively associated with WHR and BMI (p < 0.05, for both associations).ConclusionsLower folate intake and serum levels are weakly, but independently, associated with greater body weight and central adiposity in people aged 20–40. MTHFR and DHFR polymorphism seems not to have significant impact on body weight.

The Zebrafish (Danio Rerio) as a Novel Model to Study Folate-mthfr Interactions During Embryonic Development and Effect(s) on Long-Term Health

Abstract Objectives Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of the bioactive folate form, 5-methyltetrahydrofolate (5MTHF). Common polymorphisms in MTHFR limits the availability of 5MTHF and high intakes of folic acid (FA, synthetic form) may exacerbate these effects. 5MTHF is an alternative supplement to FA, but the interaction of folate form and MTHFR genotype and role in programming metabolic health has not been determined. The zebrafish (Danio rerio) is a proven model system in nutrient and drug discovery studies. The objectives of this study were to: 1) develop a mthfr zebrafish mutant model using CRISPR-Cas9 technology; and 2) identify in zebrafish the relationship between folate form (FA vs 5MTHF) and mthfr genotype on early-life development and metabolic regulation. Methods To assay the function of mthfr in vivo, we used a rapid transient knock-out approach reported to recapitulate germline zebrafish loss-of-function phenotypes. Embryos were co-injected with Cas9 protein and a set of 4 guide RNAs (4gRNA) or Cas9 protein alone (control). Zero to 5 days post-fertilization (dpf), embryos were raised in standard conditions then fed a high cholesterol diet (HCD) up to 15 dpf with a fluorescent cholesteryl BODIPY-C12. The HCD was used to induce obesity as previously reported. Global DNA methylation (5-mC%) was measured at 5 dpf and whole-body and hepatic lipid accumulation and live imaging analyses performed at 15 dpf. Results Compared to control, 4gRNA mthfr zebrafish on an HCD had enlarged liver, greater accumulation of hepatic and whole body lipids and altered lipid transport. They also had 80% lower mthfr mRNA than control zebrafish. Global methylation was ∼15% higher (P = 0.06) in 4gRNA zebrafish suggesting a compensatory dependency on an alternative methyl donor pathway during embryonic development. We are now screening germline mutant carriers and assessing folate and methylation metabolites and the interaction of folate form and genotype. Conclusions The zebrafish mthfr mutant will be a valuable model to examine the mechanisms underlining mthfr-related pathologies and provide a high-throughput in vivo system to ascertain the role of different folate forms on embryonic development and long-term health. Funding Sources CIHR-INMD; EP supported by NSERC-CGS D.

Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice

ABSTRACT Objective: Elevated homocysteine concentrations are a risk factor for stroke. A common genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR 677 C→T) results in elevated levels of homocysteine. MTHFR plays a critical role in the synthesis of S-adenosylmethionine (SAM), a global methyl donor. Our previous work has demonstrated that Mthfr +/- mice, which model the MTHFR polymorphism in humans, are more vulnerable to ischemic damage. The aim of this study was to investigate the cellular mechanisms by which the MTHFR-deficiency changes the brain in the context of ischemic stroke injury. Methods: In the present study, three-month-old male Mthfr +/- and wild-type littermate mice were subjected to photothrombosis (PT) damage. Four weeks after PT damage, animals were tested on behavioral tasks, in vivo imaging was performed using T2-weighted MRI, and brain tissue was collected for histological analysis. Results: Mthfr +/- animals used their non-impaired forepaw more to explore the cylinder and had a larger damage volume compared to wild-type littermates. In brain tissue of Mthfr +/- mice methionine adenosyltransferase II alpha (MAT2A) protein levels were decreased within the damage hemisphere and increased levels in hypoxia-induced factor 1 alpha (HIF-1α) in non-damage hemisphere. There was an increased antioxidant response in the damage site as indicated by higher levels of nuclear factor erythroid 2-related factor 2 (Nrf2) in neurons and astrocytes and neuronal superoxide dismutase 2 (SOD2) levels. Conclusions: Our results suggest that Mthfr +/- mice are more vulnerable to PT-induced stroke damage through the regulation of the cellular response. The increased antioxidant response we observed may be compensatory to the damage amount.

Influence of plasma methotrexate level and MTHFR genotype in Korean paediatric patients with acute lymphoblastic leukaemia

Whether plasma MTX concentrations and MTHFR C677T and A1298C polymorphisms could be used as a predictor of occurrence of MTX-related toxicities in Korean paediatric patients with acute lymphoblastic leukaemia (ALL) were assessed. HD-MTX related toxicities, MTHFR polymorphisms and MTX plasma concentrations following 337 HD-MTX cycles to 117 children with ALL on maintenance therapy were analyzed. A significantly higher frequency of hyperbilirubinemia (P = 0.0443) and renal toxicity (P = 0.0107) were associated with high MTX concentrations by Fisher’s exact test. Moreover, high MTX concentrations at 24 h, 48, and 72 h were significantly associated with increased frequency of vomiting (P < 0.05) and hyperbilirubinemia (P < 0.05) by Mann-Whitney U test. There was a significantly higher frequency of mucositis in patients with the MTHFR 677 TT genotype (P = 0.0273) and a significantly higher frequency of MTX dose reduction in patients with the 677 TT genotype (P = 0.0217), compared to the CC/CT genotype. Independently, plasma MTX concentrations and MTHFR C677T genotype could be useful markers for tailoring MTX dosing and monitoring adverse effects in childhood ALL HD-MTX therapy in Korean patients.

Impact of the MTHFR C677T polymorphism on one-carbon metabolites: Evidence from a randomised trial of riboflavin supplementation

Homozygosity for the C677T polymorphism in MTHFR (TT genotype) is associated with a 24–87% increased risk of hypertension. Blood pressure (BP) lowering was previously reported in adults with the TT genotype, in response to supplementation with the MTHFR cofactor, riboflavin. Whether the BP phenotype associated with the polymorphism is related to perturbed one-carbon metabolism is unknown. This study investigated one-carbon metabolites and their responsiveness to riboflavin in adults with the TT genotype. Plasma samples from adults (n 115) screened for the MTHFR genotype, who previously participated in RCTs to lower BP, were analysed for methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), betaine, choline and cystathionine by liquid chromatography tandem mass spectrometry (LC-MS/MS). The one-carbon metabolite response to riboflavin (1.6 mg/d; n 24) or placebo (n 23) for 16 weeks in adults with the TT genotype was also investigated. Plasma SAM (74.7 ± 21.0 vs 85.2 ± 22.6 nmol/L, P = 0.013) and SAM:SAH ratio (1.66 ± 0.55 vs 1.85 ± 0.51, P = 0.043) were lower and plasma homocysteine was higher (P = 0.043) in TT, compared to CC individuals. In response to riboflavin, SAM (P = 0.008) and cystathionine (P = 0.045) concentrations increased, with no responses in other one-carbon metabolites observed. These findings confirm perturbed one-carbon metabolism in individuals with the MTHFR 677TT genotype, and for the first time demonstrate that SAM, and cystathionine, increase in response to riboflavin supplementation in this genotype group. The genotype-specific, one-carbon metabolite responses to riboflavin intervention observed could offer some insight into the role of this gene-nutrient interaction in blood pressure.

A prospective cohort study of MTHFR C677T gene polymorphism and its influence on the therapeutic effect of homocysteine in stroke patients with hyperhomocysteinemia

BackgroundHyperhomocysteinemia (HHCY) is a risk factor for cardiovascular and cerebrovascular diseases. The C677T 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism increases homocysteine (HCY) levels. This study analyzed the relationship between C677T MTHFR polymorphism and the therapeutic effect of lowering HCY in stroke patients with HHCY.MethodsBaseline data were collected from stroke patients with HHCY for this prospective cohort study. The C677T MTHFR genotype was detected by polymerase chain reaction-restriction fragment length polymorphism and the therapeutic effect to reduce HCY was compared.ResultsOf 200 stroke patients 162 (81.0%) completed follow-up and were evaluated. Most of them responded well to treatment (103 cases, 63.5%), but 59 (36.4%) patients were in the poor efficacy group. There was a significant difference in terms of age (P < 0.001), hypertension (P = 0.041), hyperuricemia (P = 0.042), HCY after treatment (P < 0.001), and MTHFR genotype (P < 0.001) between the poor efficacy and effective groups, with increased frequency of the TT genotype in the poor efficacy group. Logistic regression showed that the T allele was associated with poor efficacy (OR = 0.733, 95%CI: 0.693, 0.862, P < 0.001). In the codominant model the TT genotype was associated with poor outcome (OR = 0.862, 95%CI: 0.767, 0.970, P = 0.017) and this was also the case in the recessive model (OR = 0.585, 95%CI: 0.462, 0.741, P < 0.001) but there was no association between CT and TT in the dominant model.ConclusionsThe T allele and TT genotype of the MTHFR C677T polymorphism was associated with poor HCY reduction treatment efficacy in stroke patients with HHCY.Trial registrationThe registration number of the clinical trial is ChiCTR1800020048. Registration date: December 12, 2018.

MTHFR, XRCC1 and OGG1 genetic polymorphisms in breast cancer: a case-control study in a population from North Sardinia

BackgroundDespite conflicting results, considerable evidence suggests the association between single nucleotide polymorphisms in MTHFR, XRCC1 and OGG1 genes and, risk of developing breast cancer. Here a case-control study is reported, including 135 breat cancer patients and 112 healthy women, all representative of Northern Sardinian population.MethodsPolymerase chain reaction/restriction fragment length polymorphism method was used to determine the genotypes of five polymorphisms: MTHFR C677T (rs1801133) and A1298C (rs1801131), XRCC1 Arg194Trp (rs1799782) and Arg399Gln (rs25487) and OGG1 Ser326Cys (rs1052133). Allelic, genotypic and haplotype association analyses with disease risk and clinicopathological parameters were performed.ResultsA nominally significant association with breast cancer risk was observed for MTHFR C677T polymorphism heterozygous genotype in the codominant model (OR: 0.57, 95% CI: 0.32–1.00, p = 0.049) and for Cys/Cys genotype of the OGG1 Ser326Cys polymorphism in the recessive model (OR: 0.23, 95% CI: 0.05–1.11, p = 0.0465). No significant differences were found at genotype-level for A1298C polymorphism of the MTHFR gene and Arg194Trp and Arg399Gln of the XRCC1 gene. Furthermore, the OGG1 and XRCC1 rs25487 polymorphisms were nominally associated with PgR, Her2 status and with sporadic breast cancer, respectively.ConclusionsBased on genetic characteristics of individuals included in this study, results suggest that MTHFR CT and OGG1 Cys/Cys genotypes have a protective effect that may have an influence on breast cancer risk in a representative Northern Sardinian population.

MTHFR rs1801133 polymorphism is associated with increased risk of B-cell precursor lymphoblastic leukaemia with recurrent genetic aberrations of fetal origin

BackgroundChildhood acute lymphoblastic leukaemia (ALL) is a heterogeneous disease associated with multiple risk factors including genetic susceptibility. Polymorphisms in folate genes have been associated with a protective effect against ALL, although some studies contradict these findings. We aimed to test whether there is an association between the MTHFR rs1801133 variant and the occurrence of B-cell precursor ALL (BCP-ALL) taking in account molecularly distinct subtypes of fetal origin. MethodsWe performed a case-control genotyping study with 2067 samples, 1309 ALL and 758 controls, from children aged ≤ 15 years for MTHFR rs1801133 polymorphism. Risk associations were calculated by odds ratios estimated with unconditional logistic regression, adjusted for frequency-matched ethnic groups. ResultsOverall, MTHFR rs1801133 does not impact ALL risk in children with more than 6 years of age. A significant positive association for MTHFR rs1801133 variant was found for ALL with KMT2A-r in the dominant model (adj. OR, 1.48, 95 % CI, 1.01–2.17), while ETV6-RUNX1 and Hyperdiploid subgroups have shown a borderline effect (adj. OR, 1.33, 95 % CI, 0.99–1.78). ConclusionsThe polymorphism MTHFR rs1801133 increased the risk of infant ALL in Brazilian population.

Combined Effect of HPV and Several Gene SNPs in Laryngeal Cancer.

Background and objectives: Laryngeal squamous cell carcinoma (LSCC) is one of the most common head and neck tumors. The molecular mechanism of LSCC remains unclear. The aim of this study was to evaluate the prevalence of Human papillomavirus (HPV) and single nucleotide polymorphisms (SNPs) of TP53, MDM2, MDM4, MTHFR, CASP8, and CCR5 genes in LSCC, and to assess their correlations with patient survival. Materials and Methods: 49 LSCC patients were enrolled in this study. PCR and qRT-PCR were used to detect, identify, and quantify HPV. SNPs were genotyped using PCR and PCR-RFLP. Results: By analyzing the interactions of the SNPs of the genes with clinical parameters, the majority of patients with lymph node status (N1,2) were identified as carriers of MDM2 T/G, CASP8 ins/del, CCR5 wt/wt SNP. Cluster analysis showed that patients with MDM2 T/T SNP survive longer than patients identified as CASP8 ins/ins, MTHFR C/C, and MDM4 A/A variant carriers; meanwhile, LSCC patients with MDM2 T/T polymorphic variant had the best survival. Multivariate analysis showed that HPV-positive patients without metastasis in regional lymph nodes (N0) and harboring CASP8 ins/del variant had the best survival. Meanwhile, HPV-negative patients with identified metastasis in lymph nodes (N1 and N2) and CASP8 ins/del variant had poor survival. Conclusions: This finding suggests patients survival prognosis and tumor behavior are different according HPV status, SNP variants, and clinical characteristics of the LSCC.