Methylenetetrahydrofolate Reductase 677TT Genotype Research Articles

The association between 5, 10 - methylenetetrahydrofolate reductase and the risk of unexplained recurrent pregnancy loss in China: A Meta-analysis.

Backgroud:To analyze the correlation between gene polymorphisms of 5,10- methylenetetrahydrofolate reductase (MTHFR) and risk of unexplained recurrent pregnancy loss (URPL) in Chinese women.Methods:Eligible studies were searched in Pubmed, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) databases. Established inclusion criteria were used to screening articles, subsequently evaluate the quality of the included studies, Stata 16.0 PM and RevMan 5.3 software were conducted for meta-analysis. The pooled odds ratio (OR) with 95% confidence interval (CI) was determined to assess the relationship between MTHFR and risk of URPL in Chinese women.Results:For MTHFR C677T, fifty studies were included, involving 6677 URPL cases and 8111 controls. The overall results showed that MTHFR C677T was significantly correlated with URPL risk, especially in the homozygous model (TT vs CC; OR 3.06; 95% CI 2.56–3.66). For MTHFR A1298C, twenty-first studies were included, involving 3439 URPL cases and 3155 controls. The results showed that MTHFR A1298C was also significantly correlated with URPL risk in recessive (CC vs AC + AA; OR 1.55; 95% CI 1.25–1.93) and homozygous (CC vs AA; OR 1.53; 95% CI 1.22–1.91) models. In addition, sub-group results showed that no significant difference between north and south China populations in the MTHFR gene polymorphisms and URPL risk. Of note, the patients carrying MTHFR C677T and MTHFR A1298C joint mutants had no synergistic effect (OR 2.71; 95% CI 0.84–8.70) on the occurrence of URPL compared with the wild-type homozygous genotype (MTHFR 677CC/ MTHFR 1298AA).Conclusion:Studies included in this meta-analysis suggested that MTHFR 677T allele and 677TT genotype and MTHFR 1298CC genotype were both associated with URPL; testing MTHFR C677T gene polymorphism was a more appropriate target compared with other mutations in the prediction of URPL.

Homozygosity of the TT methylenetetrahydrofolate reductase C677T genotype is an independent long-term predictor of cardiac death in patients with premature myocardial infarction

Background Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is the main genetic modulator of homocysteine. Data suggest a potential association of homozygosity for the TT MTHFR genotype with premature myocardial infarction (MI). We explored whether TT homozygosity is associated with long-term prognosis in patients with premature ST-segment elevation MI (STEMI). Methods A total of 265 consecutive patients who had survived their first STEMI ≤35 years of age were followed for a median of 8 years (5–12). Primary endpoints were cardiac death and secondary endpoints were hospitalizations for acute coronary syndrome, myocardial revascularization, arrhythmic event or ischemic stroke. Serum lipids, homocysteine, folate levels were measured at baseline and all patients were also tested for the MTHFR C677T polymorphism. Results During follow-up 14 patients died (cardiac death) [5.3%] while 84 (31.7%) met the secondary endpoints. In univariate Cox regression analysis TT homozygosity predicted the occurrence of cardiac death (Hazard ratio (HR): 4.071; 95% confidence interval (CI): 1.404–11.809, p = .010) but not the occurrence of secondary endpoints (HR: 0.877; 95% CI: 0.479–1.605, p = .669). TT homozygosity remained an independent predictor of cardiac death after adjustment for conventional risk factors (i.e., sex, diabetes mellitus, hypertension, family history of premature coronary artery disease [CAD]) [HR: 4.350; 95% CI: 1.472–12.856, p = .008]. The association also remained after adjustment for left ventricular ejection fraction or the presence of significant CAD. Conclusions Homozygosity for the TT MTHFR is an independent long-term predictor of cardiac death in patients with premature STEMI.

Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism and Infant's Anthropometry at Birth.

Identification of causal factors that influence fetal growth and anthropometry at birth is of great importance as they provide information about increased risk of disease throughout life. The association between maternal genetic polymorphism MTHFR(677)C>T and anthropometry at birth has been widely studied because of its key role in the one-carbon cycle. MTHFR(677) CT and TT genotypes have been associated with a greater risk of low birth weight, especially in case of deficient intake of folic acid during pregnancy. This study aimed to analyze the association between the maternal MTHFR(677)C>T genetic polymorphism and anthropometry at birth in a population with adequate folate consumption. We included 694 mother–newborn pairs from a prospective population-based birth cohort in Spain, in the Genetics, Early life enviroNmental Exposures and Infant Development in Andalusia (GENEIDA) project. Women were genotyped for MTHFR(677)C>T SNP by Q-PCR using TaqMan© probes. Relevant maternal and newborn information was obtained from structured questionnaires and medical records. Results showed that maternal MTHFR(677)C>T genotype was associated with newborn anthropometry. Genotypes CT or CT/TT showed statistically significant associations with increased or decreased risk of large-for-gestational-age (LGA) or small-for-gestational-age (SGA) based on weight and height, depending on the newborn’s sex, as well as with SGA in premature neonates. The relationships between this maternal genotype and anthropometry at birth remained despite an adequate maternal folate intake.

Impact of the common MTHFR 677C\u2192T polymorphism on blood pressure in adulthood and role of riboflavin in modifying the genetic risk of hypertension: evidence from the JINGO project

BackgroundGenome-wide and clinical studies have linked the 677C→T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with hypertension, whilst limited evidence shows that intervention with riboflavin (i.e. the MTHFR co-factor) can lower blood pressure (BP) in hypertensive patients with the variant MTHFR 677TT genotype. We investigated the impact of this common polymorphism on BP throughout adulthood and hypothesised that riboflavin status would modulate the genetic risk of hypertension.MethodsObservational data on 6076 adults of 18–102 years were drawn from the Joint Irish Nutrigenomics Organisation project, comprising the Trinity-Ulster Department of Agriculture (TUDA; volunteer sample) and the National Adult Nutrition Survey (NANS; population-based sample) cohorts. Participants were recruited from the Republic of Ireland and Northern Ireland (UK) in 2008–2012 using standardised methods.ResultsThe variant MTHFR 677TT genotype was identified in 12% of adults. From 18 to 70 years, this genotype was associated with an increased risk of hypertension (i.e. systolic BP ≥ 140 and/or a diastolic BP ≥ 90 mmHg): odds ratio (OR) 1.42, 95% confidence interval (CI) 1.07 to 1.90; P = 0.016, after adjustment for antihypertensive drug use and other significant factors, namely, age, male sex, BMI, alcohol and total cholesterol. Low or deficient biomarker status of riboflavin (observed in 30.2% and 30.0% of participants, respectively) exacerbated the genetic risk of hypertension, with a 3-fold increased risk for the TT genotype in combination with deficient riboflavin status (OR 3.00, 95% CI, 1.34–6.68; P = 0.007) relative to the CC genotype combined with normal riboflavin status. Up to 65 years, we observed poorer BP control rates on antihypertensive treatment in participants with the TT genotype (30%) compared to those without this variant, CT (37%) and CC (45%) genotypes (P < 0.027).ConclusionsThe MTHFR 677TT genotype is associated with higher BP independently of homocysteine and predisposes adults to an increased risk of hypertension and poorer BP control with antihypertensive treatment, whilst better riboflavin status is associated with a reduced genetic risk. Riboflavin intervention may thus offer a personalised approach to prevent the onset of hypertension in adults with the TT genotype; however, this requires confirmation in a randomised trial in non-hypertensive adults.

Folate metabolism: Impact of involved genetic variants on homocycteine and folate levels in type 2 diabetic patients with coronary artery disease

BackgroundType2 diabetes mellitus (T2DM) has severe impacts on quality of life throughout the world. Coronary artery disease (CAD) is one of the most serious microvascular complications of T2DM. ObjectiveTo explore the relationship between plasma homocysteine (Hcy) and folate levels, and their related methylenetetrahydrofolate reductase (MTHFR) C677T and reduced folate carrier-1 (RFC-1) A80G genes polymorphism in T2DM accompanied by CAD. MethodsThis case-control study enrolled 120 T2DM patients, 60 of them had CAD, and 60 healthy control subjects. Plasma Hcy and folate were measured by ELISA and genotyping was performed by PCR-RFLP. Lipid profile was analyzed by spectrophotometer. ResultsPlasma Hcy was increased and folate was decreased in both diabetic groups in relation to control group. T2DM with CAD showed significant difference with T2DM group. Hcy level was positively correlated with total cholesterol and triglycerides in T2DM and with LDL in T2DM with CAD patients. MTHFR TT and TC genotypes had significantly higher risk of CAD in T2DM. RFC-1 GG and AG genotypes were significantly higher in diabetic groups. Hcy was significantly higher and folate was lower in MTHFR677 TT + TC than that in CC genotype in T2DM with CAD. In RFC-1 GG + GA, Hcy level was higher and folate was lower than that of AA. ConclusionMTHFR and RFC-1 genetic variants are associated with high Hcy and low folate levels in T2DM with CAD patients and are related to dyslipidemia.

Homocysteinemia is Associated with the Presence of Microbleeds in Cognitively Impaired Patients

Background & ObjectiveHomocysteine is possibly associated with cerebral small vessel diseases such as leukoaraiosis, silent brain infarction and cerebral microbleeds, which are in turn associated with cognitive dysfunction. We aimed to examine the relationships between cerebral microbleeds (CMBs) and plasma total homocysteine (tHcy) level, methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and cognitive function. MethodsA total of 819 patients with memory disturbance who visited a dementia clinic consecutively were included in this study. We retrospectively collected demographic, clinical and laboratory data including tHcy level, MTHFR C677T polymorphism and Mini-Mental State Examination (MMSE). All patients underwent brain MRI including fluid attenuated inversion recovery (FLAIR) image and T2*-weighed gradient-echo (GRE) image. Logistic regression analysis was performed to test the association between risk factors and the presence of microbleeds. ResultsOne hundred and sixty-one (19.7%) patients had CMBs, of whom 88 (54.7%) had CMBs in the lobar region. CMBs were more common in older hypertensive male patients with hyperhomocysteinemia. In multivariable analysis, plasma tHcy remained an independent predictor of the presence of CMBs after adjusting other confounders (OR: 1.035, 95% CI: 1.009-1.062, p = 0.009). Higher plasma tHcy level was also associated with number of CMBs, TT MTHFR genotype, and lower MMSE scores. ConclusionsElevated plasma tHcy level is related to high prevalence of CMBs and cognitive dysfunction. Lowering plasma tHcy could be helpful in cognitively impaired patients who have CMBs or the MTHFR TT genotype.

DNA methylation of hypertension-related genes and effect of riboflavin supplementation in adults stratified by genotype for the MTHFR C677T polymorphism

BackgroundThe interaction between genetic, epigenetic and environmental factors plays an important role in the aetiology of hypertension. GWAS and observational studies link the C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) with hypertension, while riboflavin, the MTHFR cofactor, has been shown to reduce blood pressure and global DNA methylation in homozygous (TT genotype) individuals. It is currently unclear whether riboflavin modulates DNA methylation of other hypertension-related genes. ObjectivesTo compare DNA methylation of hypertension-related genes in adults stratified by MTHFR genotype and effect of riboflavin intervention in adults with the variant MTHFR 677TT genotype. MethodPyrosequencing was carried out for hypertension-related genes (ACE, AGTR1, GCK, GNA12, IGF2, MMP9 and NOS3) in blood samples from participants in previous trials (CC, n = 40; TT, n = 40). The effect of intervention with riboflavin (1.6 mg/d for16 weeks) or placebo on DNA methylation was investigated in adults with the variant MTHFR 677TT genotype (n = 80). ResultsIndividuals with the MTHFR 677TT v CC genotype had significantly higher average DNA methylation at NOS3 (+1.66%, P = 0.044). In response to riboflavin supplementation in TT individuals, there was an increase in average DNA methylation at IGF2 (+1.09%, P = 0.019) and a decrease at ACE (−0.44%, P = 0.021) in females only. Specific CpG sites were hypomethylated in GNA12 and hypermethylated in AGTR1. ConclusionThis study provides the first RCT evidence that riboflavin alters DNA methylation of hypertension-related genes in adults with the MTHFR 677TT genotype, providing some insight into mechanisms linking hypertension with the genotype-specific response of BP to riboflavin.

Methylenetetrahydrofolate reductase C667T polymorphism and susceptibility to late-onset Alzheimer's disease in the Italian population.

This study is a meta-analysis of the published studies on the relationship between methylenetetrahydrofolate reductase (MTHFR) C667T polymorphism and the risk of late- onset Alzheimer 's disease (LOAD) in Italian cohorts. We conducted a search on the electronic databases PubMed/Medline, Web of Science and Scopus. All cohort and case-control studies investigating the association between MTHFR 677T polymorphism and LOAD in Italian population published any time to May 8, 2020 were included in the analysis. From an initial screening of 136 articles, 4 were included into the systemic review. The pooled analysis based on the co-dominant model revealed that the MTHFR C677T polymorphism was associated with a significant risk of LOAD among Italian cohorts (TC vs. CC: OR=1.20, 95% CI=1.06-1.36, P=0.004, I2=0%). Conversely, the pooled analysis based on the allelic model demonstrated a non-significant relationship between the MTHFR C677T polymorphism and susceptibility to LOAD in Italians (OR: 1.25, 95% CI: 0.99-1.59, P=0.060, I2=14.6%). Moreover, Italian subjects with MTHFR 677TT genotype resulted to have a significantly increased susceptibility to LOAD (OR=1.75, 95% CI=1.23-2.50, P=0.002, I2=0%). The present meta-analysis showed only trend of association between MTHFR C677T polymorphism and LOAD in Italian population; however, it also demonstrated an increased susceptibility of LOAD in patients having MTHFR 677TT genotype. Further studies are needed to establish whether MTHFR polymorphisms can be used as non-invasive biomarker for LOAD.

Relationship of methylenetetrahydrofolate reductase C677T genetic polymorphism and oxidative changes in Egyptian patients with β-thalassemia major

Objectives To evaluate the genetic polymorphism of methylenetetrahydrofolate reductase (MTHFR) C677T among patients with beta-thalassemia major and its related oxidative changes. Background Accelerated oxidative damage is one of the hallmarks in beta-thalassemia major. Genetic polymorphism of MTHFR C677T has been shown to cause hyperhomocysteinemia, which acts as a prooxidant. Material and methods Genotyping for MTHFR C677T was evaluated by PCR-restriction fragment length polymorphism technique. Complete blood picture, hemoglobin electrophoresis, serum ferritin, and total antioxidant capacity (TAC) were determined in 60 patients with beta-thalassemia major and 20 controls of matched age and sex. Results MTHFR 677TT genotype was significantly higher among patients with beta-thalassemia major (23.3%) compared with controls (5%). There was significant decrease in TAC in thalassemic patients as compared with controls. TAC was significantly lower in TT group than both of CC and CT groups. Ferritin level was significantly higher in thalassemic group than controls. Conclusion Detection of MTHFR (C6777T) genetic polymorphism among thalassemic patients could be helpful in assessment of oxidative stress among these patients.

Effects of MTHFR C677T polymorphism on vitamin D, homocysteine and natural killer cell cytotoxicity in women with recurrent pregnancy losses.

Is there any relationship between vitamin D [25 (OH) vitamin D], total plasma homocysteine and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in women with recurrent pregnancy losses (RPL)? Women with MTHFR 677TT (homozygous mutation, TT) genotype have significantly lower vitamin D levels, higher homocysteine and natural killer (NK) cell cytotoxicities than those of women with MTHFR 677CC (wild type, CC) and 677CT (heterozygous mutation, CT) genotypes. Vitamin D insufficiency, MTHFR C677T polymorphism and hyperhomocysteinemia have been reported as risk factors for RPL. However, the relationship between these risk factors is not known in this population. This is a retrospective cross-sectional study, including 837 women with RPL, who were enrolled in Reproductive Medicine and Immunology, Chicago Medical School, between 2012 and 2017. Women with two or more RPL prior to 20 weeks of gestation were included. To investigate whether the MTHFR C677T polymorphism affects the levels of homocysteine and vitamin D as well as immune parameters in women with RPL, biochemical data, such as plasma total homocysteine and serum vitamin D levels, and immune parameters, including NK cell cytotoxicity, were analyzed by MTHFR C677T genotype (CC, CT and TT). The serum level of vitamin D in TT was significantly lower when compared with those of CT (P = 0.001) and CC (P = 0.003), while the level of homocysteine in TT was significantly higher than those in CT (P = 0.01) and CC (P = 0.01). NK cytotoxicity in TT was significantly higher than that of CC (P = 0.04) but not CT (P = 0.09). There was a significant negative correlation between the levels of vitamin D and homocysteine in TT (r = -0.357, P < 0.01). In multivariate analysis, vitamin D insufficiency (<30 ng/ml) was an independent risk factor for hyperhomocysteinemia (adjusted odds ratio 1.89, 95% CI 1.41-2.52). The study was retrospective and included only women with RPL but not healthy fertile controls. In addition, folic acid, vitamin B6 and B12 intake, which could modify the level of homocysteine and vitamin D, were not investigated. Thus, a considerable part of women might have folic acid and vitamin D supplementation and prenatal vitamin pills, and there are probable confounders in this study associated with unrestricted vitamin supplementation. Therefore, the findings should be carefully interpreted and applied to RPL women with MTHFR gene polymorphism. The findings attained in this analysis regarding the MTHFR polymorphism and its relationship with vitamin D, homocysteine and NK cytotoxicity may aid in uncovering the underlying etiology and mechanism for RPL. The study highlights an interplay between nutrition and immune responses in RPL. No external funding was received for this study. None of the authors have any conflict of interest to declare. N/A.

Homocysteine, the methylenetetrahydrofolate reductase 677C>T polymorphism and hypertension: effect modifiers by lifestyle factors and population subgroups.

Evidence linking fasting plasma total homocysteine (tHcy) and methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype with hypertension is inconsistent. Differences in B vitamin status, other lifestyle factors or their consideration in analyses might explain this. We investigated these associations in the absence of mandatory fortification with folic acid and B vitamin supplement use. A cross-sectional study was conducted in 788 adults, aged 18-75 years, randomly selected from three Catalonian town population registers. Fasting plasma folate, cobalamin, tHcy, erythrocyte folate, erythrocyte glutathione reductase activation coefficient (EGRAC, functional riboflavin status indicator; increasing EGRAC indicates worsening riboflavin status), MTHFR 677C>T and solute carrier family 1 (SLC19A1) 80 G>A genotypes were determined. Medical history and lifestyle habits were recorded. Principal tHcy determinants differed between women (age, plasma folate, plasma cobalamin, cigarettes/d) and men (MTHFR 677TT genotype, plasma folate, plasma cobalamin and CT genotype). The MTHFR 677C>T polymorphism-tHcy association (β standardised regression coefficients) was stronger in male smokers (0·52, P < 0·001) compared with non-smokers (0·21, P = 0·001) and weaker in participants aged >50 years (0·19, P = 0·007) compared with ≤50 years (0·31, P < 0·001). Hypertension was more probable in the third tHcy tertile compared with other tertiles (OR 1·9; 95 % CI 1·2, 3·0), and in participants aged ≤50 years, for the MTHFR 677TT genotype compared with the CC genotype (OR 4·1; 95 % CI 1·0, 16·9). EGRAC was associated with increased probability of hypertension in participants aged >50 years (OR 6·2; 95 % CI 1·0, 38·7). In conclusion, moderately elevated tHcy and the MTHFR 677CT genotype were associated with hypertension. The MTHFR 677C>T genotype-hypertension association was confined to adults aged ≤50 years.

DNA methylation of hypertension-related genes is influenced by the MTHFR 677TT genotype and riboflavin supplementation

AbstractIntroduction:The C677T polymorphism in the folate metabolising enzyme methylenetetrahydrofolate reductase (MTHFR) is associated with hypertension. Riboflavin acts as a cofactor for MTHFR in one-carbon metabolism which generates methyl groups for utilisation in important biological reactions such as DNA methylation. Supplementation with riboflavin has previously been shown to lower blood pressure in individuals with the MTHFR 677TT genotype. The mechanism regulating this gene-nutrient interaction is currently unknown but may involve aberrant DNA methylation which has been implicated hypertension.Objectives:The aims of this study were to examine DNA methylation of hypertension-related genes in adults stratified by MTHFR C677T genotype and the effect of riboflavin supplementation on DNA methylation of these genes in individuals with the MTHFR 677TT genotype.Materials and Methods:We measured DNA methylation using pyrosequencing in a set of candidate genes associated with hypertension including angiotensin II receptor type 1 (AGTR1), G nucleotide binding protein subunit alpha 12 (GNA12), insulin-like growth factor 2 (IGF2) and nitric oxide synthase 3 (NOS3). Stored peripheral blood leukocyte samples from participants previously screened for the MTHFR C677T genotype who participated in targeted randomised controlled trials (1.6mg/d riboflavin or placebo for 16 weeks) at Ulster University were accessed for this analysis (n = 120).Results:There were significant differences in baseline average methylation between MTHFR CC and TT genotypes at NOS3 (p = 0.026) and AGTR1 (p = 0.045) loci. Riboflavin supplementation in the TT genotype group resulted in altered average methylation at IGF2 (p = 0.025) and CpG site-specific alterations at the AGTR1 and GNA12 loci.Conclusion:DNA methylation at genes related to hypertension were significantly different in individuals stratified by MTHFR genotype group. Furthermore, in MTHFR 677TT genotype individuals, there were concurrent alterations in DNA methylation at genes linked to hypertension in response to riboflavin supplementation. This is the largest study to date to demonstrate an interaction between DNA methylation of hypertension-related genes and riboflavin supplementation in adults with the MTHFR 677TT genotype. Further work using a genome-wide approach is required to better understand the role of riboflavin in altering DNA methylation in these genetically at-risk individuals.

Central blood pressure in adults screened for a genetic polymorphism in folate metabolism

AbstractAs the primary risk factor for cardiovascular disease (CVD), hypertension is the leading cause of preventable, premature mortality globally. Hypertension, or elevated blood pressure (BP), has a number of well-established risk factors, including genetics. A common C677T polymorphism in the gene encoding the folate metabolising enzyme methylenetetrahydrofolate reductase (MTHFR) affects 10–12% of UK and Irish populations and has been linked with 24–87% increased risk of hypertension globally. Evidence from randomised controlled trials (RCTs) conducted at this Centre has shown BP to be highly responsive (by 5–13 mmHg) to supplementation with riboflavin (MTHFR co-factor), an effect confined to homozygous individuals (TT genotype). To date, our trials have focused on peripheral BP; however, additional measures of vascular health such as central pressure are reported to be more closely correlated with CVD risk. Investigation of central BP, augmentation index (AIx) and pulse pressure amplification (PPA) may thus offer further insight into the role of this gene-nutrient interaction in blood pressure. The present study aims to investigate BP, and measures of vascular health in healthy adults stratified by MTHFR 677 genotype. Apparently healthy adults aged 18–60 years were recruited from workplaces across Northern Ireland and screened for MTHFR genotype via buccal swab. Clinic BP, anthropometry and blood sample were measured in TT individuals (n 209) and age and sex-matched CC (n 98) and CT (n 102) controls. AIx and central BP were assessed using SphygmoCor® (AtCor Medical, Australia). Preliminary results demonstrate higher BP in individuals with the MTHFR 677TT genotype compared to non-TT controls (systolic BP 134.7 ± 13.8 mmHg vs 129.7 ± 12.4 mmHg, P &lt; 0.001; diastolic BP 81.6 ± 9.5 mmHg vs 79.7 mmHg ± 8.9 mmHg, P = 0.023, respectively). The MTHFR 677TT genotype group had significantly higher central systolic BP (119.4 ± 11.8 vs 116.7 ± 10.9 mmHg, P = 0.018), central pulse pressure (P = 0.006) and central mean pressure (P = 0.011) compared to the non-TT group. No significant differences for central diastolic BP, pulse pressure amplification, pulse pressure ratio and augmentation index were observed. This study confirms the phenotype of elevated BP in individuals with the C677T polymorphism in the gene encoding MTHFR. For the first time, this study reports that individuals with the MTHFR 677TT genotype have higher central systolic BP, central mean pressure and pulse pressure. Further investigations through RCTs investigating the effect of the MTHFR cofactor, riboflavin, on central blood pressure in these genetically at-risk adults are warranted.

Association Between Homocysteine Level and Methylenetetrahydrofolate Reductase Gene Polymorphisms in Type 2 Diabetes Accompanied by Dyslipidemia.

Objective To investigate the association between total homocysteine (tHcy) level in plasma and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genetic polymorphisms in a Chinese Han nationality population with type 2 diabetes mellitus (T2DM) accompanied by dyslipidemia. Methods This case-control study enrolled T2DM patients with dyslipidemia and without dyslipidemia respectively. Sanger dideoxy-mediated chain-termination method was used to detect the gene polymorphisms of MTHFR C677T and A1298C. Plasma tHcy and lipid levels were measured as well. The genotype frequency and allele frequency between the dyslipidemia and non-dyslipidemia groups were compared by using Chi-square test. Plasma tHcy level of T2DM patients who carried the different genotypes was compared by Student's t test. Results Finally, 82 T2DM patients with dyslipidemia and 94 ones without dyslipidemia were included in this study. There was a significant correlation between tHcy level and MTHFR C677T gene polymorphism in T2DM patients (t=2.27, P=0.02). Moreover, the plasma tHcy level in the dyslipidemia patients who carried MTHFR 677 TT genotype was significantly higher than that in those with CT+CC genotype (13.62±6.97 vs. 10.95±3.62 μmol/L, t=2.20, P=0.03); while for patients without dyslipidemia, comparison of the tHcy level between those who carried the above two alleles showed no significantly difference (13.34±6.03 vs. 12.04±5.09 μmol/L, t=1.08, P=0.29). Conclusion MTHFR 677TT genotype might associate with higher tHcy level in T2DM patients with dyslipidemia.

Estimated Stroke-Free Survival of Folic Acid Therapy for Hypertensive Adults: Projection Based on the CSPPT.

The CSPPT (China Stroke Primary Prevention Trial) demonstrated a significant risk reduction of first stroke in hypertensive patients treated with enalapril plus folic acid compared with those with enalapril alone, but the lifetime stroke-free survival associated with the treatment is unknown. By establishing adjusted models for competing risks and an age-based time scale using data from 19 053 participants of the CSPPT, we estimated lifetime incremental stroke-free survival for enalapril-folic acid versus enalapril alone. Compared with enalapril alone, the enalapril plus folic acid treatment projected a mean lifetime stroke-free survival gain of 1.75 months, with an interquartile range from 0.73 to 2.39 months and the maximum gain up to 12.95 months. Subgroup analyses showed greater gain in stroke-free survival in younger, male patients, those with lower baseline folate levels, higher baseline systolic blood pressure, higher baseline total cholesterol and blood glucose, and with MTHFR (methylenetetrahydrofolate reductase) C677T CT or TT genotype. Overall, besides significant benefit in certain subgroups, enalapril plus folic acid treatment for hypertensive patients is associated with a modest gain in lifetime stroke-free survival, compared with enalapril alone.

P3566Ambulatory blood pressure response to riboflavin supplementation in adults with the C677T polymorphism in the folate metabolising enzyme methylenetetrahydrofolate reductase (MTHFR)

Abstract Background Epidemiological evidence suggests that the C677T polymorphism in the folate metabolising enzyme MTHFR is associated with a 24–87% increased risk of hypertension. Riboflavin (a cofactor for MTHFR) can modify this phenotype, as demonstrated in a series of RCTs, at this centre. ABPM measures BP over 24hrs and provides a more reliable assessment of an individual's BP compared to clinic BP. Aim To investigate the effect of riboflavin supplementation on BP (by ABPM) in adults with the MTHFR 677TT genotype. Methods Adults (n=3462) were recruited and screened for the MTHFRTT genotype and those eligible (n=81), were stratified by baseline SBP and randomised to receive riboflavin (10mg/day/16weeks) or placebo. Riboflavin status was measured using the erythrocyte glutathione reductase activation coefficient (EGRac) assay and clinic and ABPM were measured in accordance with clinical guidelines. Results Mean 24hr, daytime and night-time SBP was 6mmHg higher (p&lt;0.05) in adults with the TT v CC genotype. BP response to riboflavin was strongly dependent on baseline BP. In participants with a baseline SBP≥125mmHg, riboflavin resulted in a significant BP lowering in daytime SBP (Table). Day-time SBP response to riboflavin Treatment Placebo P-value Age 48.6 (11.3) 47.8 (12.0) 0.823 Male n (%) 17 (73.9) 12 (46.2) 0.093 BMI 28.8 (3.8) 27.2 (3.1) 0.131 Riboflavin status (EGRac)† Pre 1.33 (1.28–1.38) 1.29 (1.24–1.34) Post 1.20 (1.14–1.25) 1.31 (1.25–1.36) &lt;0.001 Change −0.12 0.02 Daytime BP (mmHg)‡ Pre 137.1 (132.7–141.3) 134.7 (130.3–139.1) Post 133.0 (128.9–138.1) 134.8 (130.6–139.1) 0.036 Change −3.8 −0.2 ANCOVA, adjusting for sex. †Higher EGRac values indicate lower riboflavin status; ‡mean of participant daytime/awake hrs personalised for each participant. Conclusion This is the first study to show, using ABPM, that riboflavin supplementation, targeted at adults with the MTHFR 677TT genotype, results in significant lowering of mean, day and night BP. Given the frequency of this genotype worldwide (approximately 10%, but as high as 30% in some populations) these findings could offer a personalised approach for BP management in at-risk sub-populations. Acknowledgement/Funding This work was supported by DSM Nutritional Products, Ltd and Wellcome Trust-Wolfston Northern Ireland Clinical Research Facility are acknowledged

Evidence of a Role for One-Carbon Metabolism in Blood Pressure: Can B Vitamin Intervention Address the Genetic Risk of Hypertension Owing to a Common Folate Polymorphism?

ABSTRACTHypertension in adulthood is recognized as the leading risk factor contributing to mortality worldwide, primarily from cardiovascular disease, whereas hypertension in pregnancy leads to serious adverse fetal and maternal outcomes. This article explores the under-recognized role of one-carbon metabolism in blood pressure (BP) and the potential for folate-related B vitamins to protect against hypertension. Genome-wide association studies and clinical studies provide evidence linking the 677C→T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with BP and increased risk of hypertension and hypertension in pregnancy. A novel role for riboflavin (the MTHFR cofactor) has recently emerged, however, with evidence from randomized trials that supplemental riboflavin can lower BP specifically in adults with the variant MTHFR 677TT genotype. Further studies are required to elucidate the biological mechanisms linking one-carbon metabolism with BP and explore the effect of riboflavin in modulating the genetic risk of hypertension in early and later life.

Serum levels of miR-199a-5p correlates with blood pressure in premature cardiovascular disease patients homozygous for the MTHFR 677C > T polymorphism

This investigation profiled circulating serum concentrations of microRNAs (miRNAs) in premature cardiovascular disease (CVD) patients screened for the 677C > T polymorphism in methylenetetrahydrofolate reductase (MTHFR), a risk factor for hypertension. Serum samples from 75 premature CVD patients of known MTHFR genotype were analysed for CVD-related miRNA expression, to identify those that were associated with blood pressure. Samples were collected at baseline and following intervention with riboflavin as part of a randomized controlled trial. In patients with the MTHFR 677TT genotype, expression of miR-199a-5p in serum was inversely correlated with hypertension at baseline, and with change in blood pressure in TT genotype patients who responded to riboflavin intervention. These correlations were not observed in MTHFR 677CC genotype patients. In vitro experiments and in silico data analysis provided evidence that miR-199a-5p targets SMAD4. This is the first study to link miR-199a-5p expression with hypertension in a genetically at-risk cohort of premature CVD patients.

Abstract 198: Lifetime Clinical Benefit of Folic Acid Therapy for Primary Prevention of Stroke in Patients with Hypertension - Projection Based on the CSPPT

Background: The CSPPT (China Stroke Primary Prevention Trial) demonstrated a significant risk reduction of first stroke in hypertensive patients treated with EPFA (enalapril plus folic acid) compared to those with enalapril alone, but the life time clinical benefit associated with the use of EPFA is unknown. In this study, we evaluated and quantified the net lifetime clinical benefit of EPFA vs. enalapril alone via assessing stroke-fee life expectancy. Methods: By establishing adjusted models for competing risks and an age-based time scale using data from 19, 053 participants of the CSPPT, we estimated lifetime incremental stroke-free life expectancy for EPFA vs. enalapril alone. Results: Compared with enalapril alone, lifetime EPFA treatment projected a mean stroke-free survival gain of 1.75 months, with an interquartile range months from 0.96 to 4.06 months and the maximum gain up to 12.95 months ( Table 1 ). Subgroup analysis showed greater gain in stroke-free survival in younger male patients, and those with lower baseline folate levels, higher systolic blood pressure, higher total cholesterol and blood glucose, and with methylenetetrahydrofolate reductase (MTHFR) C677T CT or TT genotype; the net benefit of stroke-free life expectancy varies from 3.5 months to 5.3 months among subgroup ( Figure 1 ). Conclusions: Our analyses projected that compared with enalapril alone, enalapril plus folic acid treatment in patients with hypertension is associated with a modest gain in lifetime stroke-free life expectancy. Younger male patients and those with lower baseline folate levels, and higher systolic blood pressure, total cholesterol and blood glucose, and the MTHFR C677T CT or TT genotype are expected to benefit most from the treatment.

MTHFR C677T Polymorphism Is Associated with the Risk of Breast Cancer among Kurdish Population from Western Iran

Background: The key enzyme of methylenetetrahydrofolate reductase (MTHFR) is involved in DNA biosynthesis and repair. Objectives: The role of MTHFR C677T polymorphism in susceptibility to breast cancer is controversial. Methods: In the present case-control investigation, 297 individuals consisted of 100 patients with breast cancer and 197 healthy women were studied for MTHFR C677T genotypes, using PCR-RFLP method. Results: The frequency of MTHFR TT genotype was 10% in patients and 3% in controls (P = 0.008). The presence of TT genotype was associated with susceptibility to breast cancer [OR = 1.97, 95%CI: 1.16-3.36, P = 0.012]. The T allele of MTHFR was found in 30% of the patients compared to 27.6% healthy controls (P = 0.024) that enhanced the risk of breast cancer by 1.56 times (95% CI: 1.06 - 2.3, P = 0.024). There were 71 individuals (71%) with the age of breast cancer diagnosis ≤ 51 years old. Comparing patients with the age of cancer diagnosis ≤ 50 years old with those > 51 years old group indicated a higher frequency of MTHFR TT genotype in the latter (20.7%) compared to the first group (5.6%, P = 0.05). Conclusions: Our study demonstrated an association between the MTHFR C677T polymorphism with the risk of breast cancer among population of Western Iran. Also, our study suggests that the MTHFR TT genotype could be a risk factor for breast cancer in postmenopausal women.