MTHFR Genotype Research Articles

ASSOCIATION OF SINGLE-NUCLEOTIDE POLIMORPHISMS IN FOLATE PATHWAY GENES WITH THE RISK OF DIFFUSE LARGE B-CELL LYMPHOMA: META-ANALYSIS

The results of original studies often show the different effects of single nucleotide polymorphisms (SNPs) in folate pathway genes on the risk of diffuse large B-cell lymphoma (DLBCL). Meta-analysis allows integrating the accumulated data. To assess the impact MTHFR C677T and A1298C, MTR A2756G, SHMT1 C1420T, CBS 844ins68 on the risk of DLBCL, we performed a meta-analysis of the case-control studies among the Caucasian population. The 12 publications were selected for the study according to the selection criteria. Taking into account the heterogeneity of the data, the calculation was performed using a random effects model. There was no association of MTHFR A1298C, MTR A2756G, SHMT1 C1420T, CBS 844ins68 with the risk of DLBCL. The meta-analysis revealed an association of the rare genotype MTHFR 677T/T with an increased risk of DLBCL (OR 1.2 CI [1.008-1.572], p = 0.041).

Role of MTHFR C667T and MTRR A66G genes polymorphism with thyroid disorders

Thyroid disorders is the most common disease of the endocrine system. It is estimated that there are approximately 300,000 new cases of thyroid cancer worldwide. Overcome of these are females, the number of cases for thyroid disorders has been infix increasing. The aim of this study was to determine the correlation between MTHFR C677T and MTR A2756G polymorphisms involved in folic acid metabolism with thyroid disorders. We also wanted to investigate the relationship between these genetic variation and risk factors. The blood samples were collected from all cases in two different tubes: first for biochemical analysis, the second have EDTA used for DNA extraction. By Bio drop, DNA concentration and purity were measuring done, In this study be accomplished the correlation between the genetic variation of MTRR A66G gene and MTHRF C677T gene polymorphism with thyroid disorders by ARMS-PCR. In this study show increase the levels of T3 and T4 and decrease the level of TSH in patients with hyperthyroidism compare with control groups, also this table show decrease the levels of T3 and T4 but increase the level of TSH in patients with hypothyroidism compare with healthy peoples. As well as the result showed increase in levels of glucose, cholesterol and triglyceride in patients with hypothyroidism compare with healthy people, Concerning in hyperthyroidism we showed decrease in levels of glucose, cholesterol and triglyceride compare with healthy people. The association between MTHFR C677T and MTRR A66G polymorphisms and the risk of thyroid disorders showed. The 677TT genotype was associated with increased risk for both hypothyroidism (30 %) and hyperthyroidism (10 %) but in different ratio. The 677TC genotype be found in this study have same influence in hypothyroidism (60 %) and hyperthyroidism (60 %) and the 677CC genotype present in result but have different effect on study groups in hypothyroidism (10 %) and hyperthyroidism (30 %). The result also show the genotype ratio of MTRR A66G gene in cases. The GG genotype was associated with thyroid disorders for both hypothyroidism (60 %) and hyperthyroidism (40 %) but in different ratio. The AG genotype be found in this study have same influence in hypothyroidism (20 %) and hyperthyroidism (20 %) and the AA genotype present in result but have different effect on study groups in hypothyroidism (20 %) and hyperthyroidism (40 %). The study has found that the correlation and interaction between MTHFR and MTRR genes polymorphism with thyroid disorders. In addition, we found the genotype (TT) MTHFR C677T polymorphism and the genotype (GG) for MTRR A66G increased risk factors in thyroid disorders.

Influence of genetic polymorphisms on waterpipe smoking phenotypes

Waterpipe smoking popularity is increasing worldwide and especially in the middle eastern societies. Its specific social and physical features in addition to its harm misperception are making it a trendy smoking tool. Like cigarette, waterpipe exhibit dependence and craving behaviors but studies addressing the inter-individual variability shaping this trend are lacking. Therefore, we analyzed the SNPs of dopamine receptors D2, COMT and MTHFR enzymes responsible for dopamine metabolism, and assessed the association of these polymorphisms with the waterpipe smoking behavior. For this purpose, our study examined the genotype and allele frequency of DRD2 (rs6277), COMT (rs 4680), and MTHFR (rs1801133). We tested for a potential influence of the above men04tioned SNPs on the manifestation of waterpipe smoking behavior in a sample of 451 Lebanese adults recruited from community pharmacies in Mount Lebanon and Beirut districts. Our findings showed that DRD2 (rs6277) T allele was associated with a lower TCQ score and COMT (rs 4680) A allele was associated with a lower duration of waterpipe smoking. Whereas MTHFR (rs1801133) T allele was associated with a higher LWDS score. Findings provide evidence of association between MTHFR rs1801133 and WP dependence, COMT p.Val158Met with the duration of WP smoking and DRD2 rs6277 with the level of waterpipe craving. Further genetic association studies are needed to cover all the waterpipe smoking aspects.

Riboflavin Is an Important Determinant of Vitamin B-6 Status in Healthy Adults

Riboflavin is required to generate the active form of vitamin B-6 (pyridoxal 5'-phosphate; PLP) in tissues, but the relevance of this metabolic interaction for nutritional status of vitamin B-6 is unclear because riboflavin biomarkers are rarely measured in human studies. The purpose of this study was to identify the determinants of biomarkers of vitamin B-6 and riboflavin status and to examine the relationship between these nutrients in healthy adults. Multiple linear regression was performed on observational data in 407 healthy adults aged 18-92 y who did not use B-vitamin supplements. Vitamin B-6 status was assessed by plasma PLP concentrations and erythrocyte glutathione reductase activation coefficient (EGRac) was used as a functional indicator of riboflavin status. Dietary intakes of vitamin B-6 and riboflavin were below the average requirements in 10% and 29% of participants, respectively. Suboptimal status of vitamin B-6 (PLP ≤30.0nmol/L) was more prevalent in adults aged ≥60 y than in younger participants (i.e., 14% compared with 5%), whereas a high proportion (i.e., overall 37%) of both age groups had deficient riboflavin status (EGRac ≥1.40). In multiple regression analysis, EGRac (P=0.019) was a significant determinant of plasma PLP, along with dietary vitamin B-6 intake (P=0.003), age (P<0.001), BMI (kg/m2) (P=0.031), and methylenetetrahydrofolate reductase gene (MTHFR) genotype (P<0.001).Significant determinants of EGRac were dietary riboflavin intake (P<0.001), age (P<0.001)and MTHFR genotype (P=0.020). Plasma PLP showed a stepwise decrease across riboflavin status categories from optimal (EGRac ≤1.26) to low (EGRac 1.27-1.39) to deficient status (P=0.001), independent of dietary vitamin B-6 intake. The findings are consistent with the known metabolic dependency of vitamin B-6 on riboflavin status and indicate that riboflavin may be the limiting nutrient, particularly in older people, for maintaining adequate vitamin B-6 status.

Nonsyndromic orofacial clefts in Chile: LINE-1 methylation and MTHFR variants.

Aim: To evaluate the risk of nonsyndromic orofacial clefts (NSOFCs) associated withLINE-1 methylation, as amarker of global DNA methylation, and the effect of MTHFR functional variants on this variable. Patients & methods: LINE-1 methylation was evaluated by bisulfite modification coupled to DNA pyrosequencing in 95 NSOFC cases and 95 controls. In these subjects, MTHFR genotypes for variants c.C677T (rs1801133) and c.A1298C (rs1801131) were obtained. Results: Middle levels (second tertile) of LINE-1 methylation increase the risk of NSOFCs. In addition, LINE-1 methylation depends on c.A1298C genotypes in controls but not in cases. Conclusion: A nonlinear association between global DNA methylation and NSOFCs was detected in this Chilean population, which appears to be influenced by MTHFR functional variants.

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.

Maternal folate, one-carbon metabolism and pregnancy outcomes.

Single nucleotide polymorphisms and pre‐ and peri‐conception folic acid (FA) supplementation and dietary data were used to identify one‐carbon metabolic factors associated with pregnancy outcomes in 3196 nulliparous women. In 325 participants, we also measured circulating folate, vitamin B12 and homocysteine. Pregnancy outcomes included preeclampsia (PE), gestational hypertension (GHT), small for gestational age (SGA), spontaneous preterm birth (sPTB) and gestational diabetes mellitus (GDM). Study findings show that maternal genotype MTHFR A1298C(CC) was associated with increased risk for PE, whereas TCN2 C766G(GG) had a reduced risk for sPTB. Paternal MTHFR A1298C(CC) and MTHFD1 G1958A(AA) genotypes were associated with reduced risk for sPTB, whereas MTHFR C677T(CT) genotype had an increased risk for GHT. FA supplementation was associated with higher serum folate and vitamin B12 concentrations, reduced uterine artery resistance index and increased birth weight. Women who supplemented with <800 μg daily FA at 15‐week gestation had a higher incidence of PE (10.3%) compared with women who did not supplement (6.1%) or who supplemented with ≥800 μg (5.4%) (P < .0001). Higher serum folate levels were found in women who later developed GDM compared with women with uncomplicated pregnancies (Mean ± SD: 37.6 ± 8 nmol L−1 vs. 31.9 ± 11.2, P = .007). Fast food consumption was associated with increased risk for developing GDM, whereas low consumption of green leafy vegetables and fruit were independent risk factors for SGA and GDM and sPTB and SGA, respectively. In conclusion, maternal and paternal genotypes, together with maternal circulating folate and homocysteine concentrations, and pre‐ and early‐pregnancy dietary factors, are independent risk factors for pregnancy complications.

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.

Gene polymorphism of blood coagulation factors and endothelial dysfunction in early and late preeclampsia.

The aim of our study was to find out the influence of gene polymorphisms of coagulation factors, endothelial dysfunction and regulators of blood pressure in early (EPE) and late preeclampsia (LPE). The study of genetic polymorphisms of blood coagulation factors and fibrinolysis (1691 G/A factor V Leiden (FVL), 20210 G/A prothrombin, -675 5G/4G PAI-1, 455 G/A fibrinogen β), endothelial dysfunction (192 Q → R paraoxonase 1, 677 C/T MTHFR, arterial pressure regulator (235 M/T angio­tensinogen II (AGT II)) using an PCR was performed. A prospective cohort study of 39 women with EPE, 93 with LPE and 44 pregnant women with a physiological pregnancy (C group) was conducted. The average gestational age at the time of delivery in EPE group was lower than in LPE and control group (p&lt;0.001). In group with EPE new-borns had low weight-growth characteristics, low grade by the Apgar scale and foetal distress (38.5% vs. 9.7%, p&lt;0.05). Caesarean section in EPE group was performed by 2.25 times more often than in control group and by 2,13 times than in LPE group (p&lt;0,05). It was detected that the number of 1691 GA FVL heterozygote carriers in the group with EPE was significantly higher than in LPE group (p&lt;0.05, OR=3.65, 95% CI 1.5-8.9) and control group (6.04, 1.7-21.6). The number of 20210 GG homozygotes and 20210 GA heterozygotes in prothrombin gene was probably lower in EPE group compared with the LPE and control group (0.03, 0.002-0.49, and 0.18, 0.06-0.53, respectively). It was established increase in frequency of 677 TT MTHFR genotype in EPE compared with control group (17.27; 0.9-317). Also, the carriers of 235T allele AGT II gene have an increased risk of EPE and PPE development (2.25, 1.2-4.2), (1.9, 1.1-3.3) respectively. The allele -455A of fibrinogen β gene increases the chances of developing EPE by 4.4 times (2.0-9.5), and LPE by 3.5 times (1.7-7.1). Risk factors that significantly increase the chances of developing early preeclampsia were identified: allele 1691 A of FV Leiden (5.96, 1.5-8.9), allele 20210 A of prothrombin (39.8, 2,3-679), 677T MTHFR (2.5, 1.18-5.3). In was detected that other researched polymorphisms between groups with PE were not significantly different and did not affect on time of preeclampsia development.

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.

Effects of 12-Week Multivitamin Supplementation on Serum Folate Levels in Pre-Menopausal Females

Abstract Objectives We determined if multivitamin supplementation (MV) affected serum folate levels in women during a 12-week intervention, and if genotypes affected these outcomes. Methods Women (21–40 years old) were recruited from the local community. PRE testing occurred between 0600–0900 AM 5 ± 2 days following each participants’ last menstrual cycle, and involved a buccal cell collection and a fasted blood draw. Participants were then randomly assigned in a double-blinded fashion to the MV group (n = 43) or placebo group (n = 51). MV (per 2 beadlets-in-capsule serving) contained 50 mcg vitamin D3, 6.7 mg alpha tocopherol of vitamin E as mixed tocopherols, 90 μg vitamin K2 MK7, 600 μg 5-methyltetrahydrofolate, 8 μg B12, 8 mg iron, 50 mg magnesium, 1 mg boron, and 320 mg omega-3 fatty acids. The placebo capsules contained safflower oil and cellulose. Participants consumed two capsules per day with breakfast for 12 weeks. Following the intervention, participants reported to the laboratory for POST testing. Serum folate analyses were performed at a hematology laboratory (East Alabama Medical Center, Opelika, AL, USA). SNPs related to folate metabolism (MTHFR rs1801133, MTHFR rs1801131, MTHFR rs2274976, MTRR rs1801394) were interrogated using the Axiom PMDA.r6 array (Thermo Fisher Scientific, Waltham, MA, USA). Results A group × time interaction was observed for serum folate levels and dietary folate intake (P &amp;lt; 0.001). MV supplementation increased serum folate levels from PRE to POST (P &amp;lt; 0.001), whereas no change occurred in the placebo group (P = 0.345). MV supplementation also increased the PRE to POST intakes of folate (P &amp;lt; 0.001), whereas these values were not affected in the placebo group (P = 0.576). MV supplementation increased serum folate levels regardless of MTHFR genotype. The MTRR rs1801394 genotype showed a genotype x time interaction (P = 0.049); specifically, folate levels increased in the AG and AA genotypes (P &amp;lt; 0.05), but not the GG genotype (P = 0.080). Conclusions MV supplementation increases serum folate levels. While the interrogated MTRR genotype may play a role regarding the efficacy of MV supplementation, these data are preliminary given the limited n-size. Funding Sources Funding was provided to MDR, RRA, and KCY by Ritual, Inc. Support was also provided by The GHT Companies, and Kappa BioSciences.

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.

Влияние полиморфизмов С677Т и А1298С гена MTHFR на репродуктивную функцию мужчин

the distribution of C677T (rs1801133) and A1298C (rs1801131) polymorphisms of the MTHFR gene among infertile and fertile men in the Moscow region and to identify a possible Association of these polymorphisms with the risk of pathospermia. the study included 127 infertile men with different forms of pathospermia and 68 fertile men (with one or more children). Genotyping of polymorphisms (C677T and A1298C) gene MTHFR was performed by real-time polymerase chain reaction (PCR-RV). Analysis of the distribution of MTHFR genotypes (C677T and A1298C) revealed no significant differences in the distribution of genotypes in groups of infertile and fertile men. The frequency of minor allele 1298S in asthenospermia was 52%, in teratospermia was 36% and in men with azzospermia - 33% (2=8.67; p=0.003). To date, there are no published results on the study of the Association of polymorphisms of folate-metabolizing enzyme genes with the development of pathospermia among men in the Moscow region. The results of our study demonstrate that 1298 polymorphism of the MTHFR gene may be involved in the etiology of male infertility in patients of the Moscow region. Comparative analysis of gene and genotype frequencies by the studied polymorphisms in infertile men with different forms of pathospermia showed an associative relationship of allele 1298C of MTHFR gene with the risk of asthenozoospermia (p<0.05).

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.

Genetic and environmental factors associated with homocysteine concentrations in a population of healthy young adults. Analysis of the MAGNETIC study

Background and aimsElevated homocysteine concentration is associated with a higher risk of cardiovascular disease. The aim of our study was to determine the environmental and genetic factors associated with serum homocysteine concentration in healthy young adults. Moreover, we aimed to determine the cutoff value of homocysteine concentration for predicting unfavorable MTHFR genotype and to investigate whether this association is modified by dietary patterns and serum folate status. Methods and resultsA total of 744 healthy individuals, aged 18–35 years, were included in the study. Diet quality was assessed by establishing diet quality scores and adherence to the pro-Healthy Diet Index (pHDI) and non-Healthy Diet Index (nHDI). Genotyping was performed using the TaqMan method.Multivariate analysis showed that pHDI, creatinine, folate concentrations, and the T/T genotype of the C677T polymorphism in MTHFR, as well as the interaction between the T/T genotype of MTHFR (C677T polymorphism) and folate level, were most strongly related to homocysteine concentrations. The specificity of a homocysteine >13.1 μmol/l in predicting T/T homozygous status was 76% (area under the curve 0.68). ConclusionHealthy dietary patterns, folate, and creatinine levels, as well as the C677T polymorphism, proved to be the strongest predictors of homocysteine concentrations. T/T genotype of MTHFR modifies the relationship between folate and homocysteine.

MTHFR, TYMS and SLCO1B1 polymorphisms and adverse liver effects of methotrexate in rheumatoid arthritis.

Aims: To investigate whether variants of MTHFR, TYMS and SLCO1B1 are associated with ALT elevation in rheumatoid arthritis patients starting methotrexate (MTX). Patients & methods: Clinical and laboratory data were collected from the start of MTX treatment. Genotyping of MTHFR, TYMS and SLCO1B1 was performed. Univariate and multiple logistic regression were used for statistical analysis. Results: 34 out of 369 patients experienced ALT >1.5 × ULN less than 6 months from start. MTHFR A1298C (rs1801131) was nominally associated with an ALT >1.5 × ULN within 6 months after the start of MTX (OR=1.7 [95% CI: 1.04-2.9]; p=0.03), but did not pass correction for multiple testing.A multiple model containing MTHFR 1298C and clinical factors predicted the outcome (C-statistic 0.735). TYMS and SLCO1B1 were not associated with the outcome. Conclusions: A model containing MTHFR 1298C and clinical factors might predict risk of early ALT elevation.

Associations between B vitamin and amino acid intake, MTHFR genotype, atherogenic indices, and homocysteine levels in postmenopausal women

AbstractIt has been hypothesized that insufficiency of one-carbon metabolism may aggravate lipid metabolism disturbances. Lipid metabolism abnormalities and metabolic syndrome (MetS)—which is associated with abnormally high levels of triglycerides (TG) and low levels of high-density lipoproteins (HDL)—often occur in postmenopausal women. The purpose of this study was thus to determine the relationships between amino acid and B vitamin intake, MTHFR genotype, lipid profile, and atherogenic indices in postmenopausal women.131 postmenopausal women were enrolled for the study. The mean macronutrient, amino acid, and B vitamin intake was evaluated using dietary records. Lipid profile and concentrations of apolipoprotein A1 (ApoA1) and B (ApoB) in serum were measured using the colorimetric method. The total homocysteine (tHcy) and glutathione (GSH) level in plasma were measured using high-performance liquid chromatography. MTHFR genotype (rs1801133) was determined using a single tube TaqMan SNP Genotyping Assay. We calculated atherogenic indices, such as Castelli's risk index I and II (CRI-I and CRI-II), the atherogenic coefficient (AC), and the TG/HDL ratio.No association was found between MetS and tHcy or GSH concentrations. MTHFR genotype and folate intake also did not affect tHcy, GSH, lipid profile, or atherogenic indices. Subjects with tHcy levels over the median had lower total protein intake, lower animal protein/plant protein ratio, lower protein/carbohydrates ratio, and higher amino acid intake (methionine, lysine, arginine, glycine, and tryptophan) than did subjects with lower tHcy levels. Women who failed to meet their vitamin B12 intake needs had almost 40% higher levels of tHcy than women who did met those needs.MTHFR genotype, folate intake, and tHcy levels in plasma are not associated with lipid metabolism in postmenopausal women. tHcy levels may depend on the intake of vitamin B12, and of protein or particular amino acids.The project was financed by the National Science Centre, Poland (grant number 2015/17/N/NZ9/04133).

Investigation of Blood Pressure during the First Trimester of Pregnancy in relation to the MTHFR C677T Polymorphism

AbstractThe common C677T polymorphism in the MTHFR gene encoding the folate-metabolising enzyme methylenetetrahydrofolate reductase is implicated in hypertension and hypertension in pregnancy. Hypertension affects up to 15% of all pregnancies and has been identified as a leading cause of maternal and neonatal morbidity and mortality worldwide. We previously reported higher systolic and diastolic blood pressure (BP) in non-pregnant women with the variant MTHFR 677TT genotype compared to CT/CC genotypes. In addition, randomised controlled trials (RCTs) in non-pregnant hypertensive adults from our Centre demonstrated that supplemental riboflavin (co-factor for MTHFR) lowers BP specifically in those with the TT genotype. However, the role of this common folate polymorphism and its interaction with riboflavin during pregnancy remains unclear. The aim of this study was to investigate the impact of MTHFR genotype and riboflavin status on BP in pregnancy. Data were generated from the ongoing Optimal Nutrition for the Prevention of Hypertension (OptiPREG) project. Pregnant women were recruited at the end of the first trimester from antenatal clinics in Northern Ireland and in the Republic of Ireland. Participants were screened for MTHFR genotype and BP was measured according to current clinical guidelines. Biomarker status of riboflavin was determined using the erythrocyte glutathione reductase activation coefficient (EGRac), a functional assay with higher EGRac values representing a lower status. Overall, 117 (11.6%) participants were identified with the variant MTHFR 677TT genotype. Both systolic and diastolic BP decreased from 8th to 16th gestational week (GW), however, this typical BP pattern was not observed in the TT genotype group. After adjusting for maternal age, GW and body mass index, women with the TT genotype at 12th GW had higher mean systolic (P 0.035) and diastolic (P 0.034) BP. When the results at the 12th GW were stratified by riboflavin status, the BP phenotype owing to this polymorphism was evident only among women with lower status (i.e. EGRac &gt; 1.30), with mean (SEM) systolic BP of 120.4 (3.1) mmHg compared to 112.6 (2.5) mmHg in those with higher status (EGRac ≤ 1.30) within the TT genotype group; in contrast, low versus high riboflavin status had no impact on BP in CT/CC genotype groups. These results suggest that MTHFR genotype influences BP during pregnancy and that riboflavin can exert an important modulating effect on BP in women with TT genotype. An RCT is required to fully investigate the role of MTHFR genotype and its interactive effect with riboflavin in BP during pregnancy.

Evaluation of Hematological Parameters in the Genetic Prospective in Epileptic Patients of Khyber Pakhtunkhwa.

BackgroundEpilepsy is a treatable disease, but unfortunately a treatment gap exists in epileptic patients, especially in developing countries, due to adverse effects of antiepileptic drugs and polymorphisms in genes. Carbamazepine is the most commonly used medication in epilepsy, but is related to some serious and rare adverse effects. The aim of the study was to investigate the effect of folate metabolizing genes (MTHFR and DHFR) polymorphisms on different parameters of complete blood count in patients who were treated with carbamazepine and valproic acid.Materials and methodsBlood samples from 267 epileptic patients were collected on consent and surrogate consent forms. The blood was analyzed for changes in different parameters in complete blood count through a blood analyzer. The MTHFR gene was genotyped using the RFLP method. The data were analyzed using GraphPad Prism 6.ResultsThe homozygous mutant genotype (677CT) of the methylenetetrahydrofolate reductase enzyme (MTHFR C677T) gene significantly affects the level of hemoglobin (P=0.12), hematocrit (P=0.008) and mean corpuscular hemoglobin (P=0.01) compared to the homozygous wild genotype (677CC) and heterozygous mutant genotype (677CT) of the MTHFR (C677T) gene. However, the heterozygous genotype (1298AC) of MTHFR (A1298C) gene affect the total leukocyte count (P=0.037) level significantly.ConclusionChanges in different parameters of complete blood count were statistically significant but clinically insubstantial decreases in different parameters of complete blood count indexes.