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MTHFR 677C → T genotype modulates the effect of a 5-year supplementation with B-vitamins on homocysteine concentration: The SU.FOL.OM3 randomized controlled trial.
Fezeu, LK, Ducros, V, Guéant, JL, Guilland, JC, Andreeva, VA, Hercberg, S, Galan, P
PloS one. 2018;(5):e0193352
Abstract
AIMS: To study how MTHFR 677C→T genotype modulates the effect of supplementation with B-vitamins on total homocysteine (tHcy) and B-vitamin concentrations. METHODS 2381 patients with a personal history of cardiovascular disease were randomly assigned to one of four groups: 1) B-vitamins alone (560 μg of 5-methyl-THF, 3 mg of vitamin B6 and 20 μg of vitamin B12), 2) n-3 fatty acids alone (600 mg of EPA and DHA in a 2:1 ratio), 3) B-vitamins and n-3 fatty acids, and 4) placebo. Participants were followed up for 4.7 years. At baseline and annually thereafter, biological parameters were assessed. Multivariate and linear mixed models were fit to study the interaction between B-vitamins and MTHFR genotype. RESULTS Among supplemented participants, concentrations of all three B-vitamins increased during the first year (all p<0.0001) across MTHFR genotype categories. tHcy decreased by 26.3% during the first year (p<0.0001), then steadily increased throughout the 5 years (ptrend<0.001). However, at the end of follow-up, that increase was smaller among TT than among CT or CC subjects (pinteraction<0.02). At baseline, the difference in tHcy concentrations between TT homozygous and CC homozygous subjects was 2.33 μmol/l (p<0.001). After 5 years, that difference was reduced to 1.06 μmol/l and remained statistically significant (p<0.001). CONCLUSION Participants with the TT genotype exhibited a lower 5-year decrease in tHcy concentrations following a B-vitamin supplementation than did participants with the CC or CT genotype. CLINICAL TRIAL REGISTRATION Current Controlled Trials # ISRCTN41926726.
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The modifying effect of the MTHFR genotype on the association between folic acid supplementation and pulse wave velocity: Findings from the CSPPT.
Yang, X, Zhang, M, Song, R, Liu, C, Huo, Y, Qian, G
Cardiovascular therapeutics. 2018;(6):e12473
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Abstract
OBJECTIVE In a subgroup analysis of the China Stroke Primary Prevention Trial, we aimed to explore the impact of folic acid supplementation on arterial stiffness and assess the modifying effect of the methylenetetrahydrofolate reductase (MTHFR) gene in Chinese patients with hypertension. METHODS This prospective study enrolled 2529 hypertensive Chinese patients. Participants were randomized to receive treatment with either a combination of enalapril and folic acid or enalapril. Brachial-ankle pulse wave velocity (PWV) was measured by trained medical staff using PWV instruments at both baseline and exit visits, approximately 5 years after enrollment. This trial was registered with clinicaltrials.gov (NCT00794885). RESULTS During the follow-up, change in folate was significantly and independently correlated with change in ba-PWV in study patients (β = -1.31, P < 0.001). Individuals with CC genotype had a significantly greater PWV response to folic acid supplementation than did carriers of the T allele (β = -2.79, P < 0.001 for CC homozygotes compared with β = -0.56, P = 0.464 for TT homozygotes). The positive effect of folic acid on improved PWV was modified by the MTHFR genotype (P for interaction = 0.034). CONCLUSION In a subgroup of Chinese hypertensive patients who had received 5-year antihypertensive therapy, increases in folate status were associated with higher reductions in PWV, and individuals with the CC genotype showed greatest PWV response to folic acid supplementation.
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The Methylenetetrahydrofolate Reductase C677T Polymorphism and Risk for Late-Onset Alzheimer's disease: Further Evidence in an Italian Multicenter Study.
Stoccoro, A, Tannorella, P, Salluzzo, MG, Ferri, R, Romano, C, Nacmias, B, Siciliano, G, Migliore, L, Coppedè, F
Journal of Alzheimer's disease : JAD. 2017;(4):1451-1457
Abstract
BACKGROUND A functional polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, namely C677T (rs1801133), results in increased Hcy levels and has been associated with risk of late-onset Alzheimer's disease (LOAD). Many investigators reported association between rs1801133 and LOAD risk in Asian populations and in carriers of the apolipoprotein E (APOE) ɛ4 allele, but recent meta-analyses suggest a contribution also in other populations, including Caucasians and/or northern Africans. OBJECTIVE To further address this issue, we performed a relatively large case-control study, including 581 LOAD patients and 468 matched controls of Italian origin. APOE data were available for a subgroup of almost 600 subjects. METHODS Genotyping for rs1801133 was performed with PCR-RFLP techniques. RESULTS In the total population, the MTHFR 677T allele (OR = 1.20; 95% CI = 1.01-1.43) and carriers of the MTHFR 677T allele (CT+TT versus CC: OR = 1.34; 95% CI = 1.03-1.73) resulted in increased LOAD risk. Similarly, in APOEɛ4 carriers, we observed an increased frequency of MTHFR 677CT carriers (CT versus CC: OR = 2.82; 95% CI = 1.25-6.32). Very interestingly, also in non-APOEɛ4 carriers, both MTHFR 677T allele (OR = 1.38; 95% CI = 1.03-1.85) and MTHFR 677TT genotype (OR = 2.08; 95% CI = 1.11-3.90) were associated with LOAD. All these associations survived after corrections for age, gender, and multiple testing. CONCLUSIONS The present results suggest that the MTHFR C677T polymorphism is likely a LOAD risk factor in our cohort, either in APOEɛ4 or in non-APOEɛ4 carriers.
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Parental Genetic Variants, MTHFR 677C>T and MTRR 66A>G, Associated Differently with Fetal Congenital Heart Defect.
Guo, QN, Wang, HD, Tie, LZ, Li, T, Xiao, H, Long, JG, Liao, SX
BioMed research international. 2017;:3043476
Abstract
BACKGROUND Congenital heart defect (CHD) is one of the most common birth defects in the world. The methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes are two of the most important candidate genes for fetal CHD. However, the correlations between the two genes and fetal CHD were inconsistent in various reports. Therefore, this study is aimed to evaluate the parental effects of the two genes on fetal CHD via three genetic polymorphisms, MTHFR 677C>T (rs1801133), MTHFR 1298 A>C (rs1801131), and MTRR 66A>G (rs1801394). METHODS Parents with pregnancy history of fetal CHD were divided into two subgroups: ventricular septal defect (VSD) (21) and non-VSD groups (78). VSD, non-VSD, and 114 control parents (controls) were analyzed in this study. Genotyping of these genetic polymorphisms was done by sequencing. RESULTS The MTHFR 677C>T polymorphism of either mothers or fathers was independently associated with fetal non-VSD (P < 0.05) but not VSD, while the MTRR 66A>G polymorphism was independently associated with fetal VSD (P < 0.05) but not non-VSD. No significance was found for MTHFR 1298A>C polymorphism. CONCLUSION In either maternal or paternal group, the MTHFR 677C>T polymorphism was independently related to fetal non-VSD, while the MTRR 66A>G polymorphism was independently related to fetal VSD.
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Interaction between MTHFR 677C>T and periconceptional folic acid supplementation in the risk of Hypospadias.
Dokter, EM, van Rooij, IA, Wijers, CH, Groothuismink, JM, van der Biezen, JJ, Feitz, WF, Roeleveld, N, van der Zanden, LF
Birth defects research. Part A, Clinical and molecular teratology. 2016;(4):275-84
Abstract
BACKGROUND Hypospadias is a congenital malformation with both environmental factors and genetic predisposition involved in the pathogenesis. The role of maternal periconceptional folic acid supplement use in the development of hypospadias is unclear. As folate levels may also be influenced by the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, we hypothesize that a gene-environment interaction between this polymorphism and folic acid use is involved in the etiology of hypospadias. METHODS We conducted a case-control study among 855 hypospadias cases and 713 population-based controls from the AGORA data- and biobank. Folic acid supplement use was derived from maternal questionnaires and infant and maternal DNA was used to determine the MTHFR C677T polymorphism using Taqman assays. We performed separate analyses for different hypospadias phenotypes (anterior/middle/posterior). RESULTS Hypospadias was neither associated with folic acid use or the MTHFR C677T polymorphism, nor with their interaction. However, we did find an association with middle hypospadias when no supplements were used (odds ratio = 1.6; 95% confidence interval, 1.1-2.4), especially in infants carrying the CT/TT genotype (odds ratio = 2.5; 95% confidence interval, 1.4-4.7). In addition, more infants with these genotypes seemed to have posterior hypospadias, regardless of folic acid use. CONCLUSION Our study does not suggest a major role for folic acid supplements or the MTHFR C677T polymorphism in the etiology of hypospadias in general, but not using folic acid and/or carrying the MTHFR C677T polymorphism may be associated with middle and posterior hypospadias. Therefore, we stress the importance of studying gene-environment interactions preferably in stratified analyses for different hypospadias phenotypes.
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Association of the MTHFR Gene C677T Polymorphism with Breast Cancer in a Turkish Population.
Kaya, EF, Karakus, N, Ulusoy, AN, Özaslan, C, Kara, N
Oncology research and treatment. 2016;(9):534-8
Abstract
BACKGROUND Breast cancer is the most common cancer among women. 1 in every 8 women in the United States have a lifetime risk of getting breast cancer. MTHFR is a key enzyme that regulates the folate metabolism which has an important role in DNA synthesis, repair, and methylation. The aim of the current study was to analyze the association between the MTHFR gene C677T (Ala222Val, rs1801133) polymorphism and breast cancer. PATIENTS AND METHODS 199 breast cancer patients and 195 healthy controls were included in this study. The MTHFR gene C677T polymorphism was analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) methods. A meta-analysis including 707 breast cancer patients and 880 controls from Turkish populations was also carried out. Statistical analyses were performed using the χ2 test. RESULTS No statistically significant differences in allele and genotype frequencies were observed between patients and controls (p > 0.05). Although not statistically significant, TT homozygous variants were encountered more frequently in patients than in controls. A statistically significant association was observed between the MTHFR gene C677T polymorphism and the tumor histology of breast cancer patients (p = 0.038). The results of the meta-analysis suggested that there was a high association between breast cancer and the MTHFR gene C677T polymorphism in Turkish populations (p < 0.0001). CONCLUSION In our study, we did not find any association between the MTHFR gene C677T polymorphism and breast cancer. However, a meta-analysis of the 6 association studies carried out in Turkish populations with 707 patients and 880 controls showed a significant association between breast cancer and the MTHFR gene C677T polymorphism.
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Alcohol consumption, genetic variants in the alcohol- and folate metabolic pathways and colorectal cancer risk: the JPHC Study.
Svensson, T, Yamaji, T, Budhathoki, S, Hidaka, A, Iwasaki, M, Sawada, N, Inoue, M, Sasazuki, S, Shimazu, T, Tsugane, S
Scientific reports. 2016;:36607
Abstract
The association between alcohol intake and colorectal cancer (CRC) may vary secondary to single nucleotide polymorphisms (SNPs) in two pathways related to alcohol intake. 375 cases of CRC were identified among 38 373 Japan Public Health Center-based prospective Study (JPHC Study) participants who had returned a baseline questionnaire, reported no diagnosis of any cancer and provided blood samples. For each case, two controls were selected on matching variables. Logistic regression models were used to determine matched Odds Ratios (OR) and 95% Confidence Intervals (CI) for the association between alcohol consumption, genetic polymorphisms of enzymes in the alcohol- and folate metabolic pathways (e.g. methylenetetrahydrofolate reductase (MTHFR) rs1801133) and CRC risk. Compared to never/occasional alcohol intake, moderate to heavy alcohol intake was associated with CRC (OR = 2.12, 95% CI, 1.34-3.36). When compared to the CC genotype, the MTHFR rs1801133 CT/TT genotype was inversely associated with CRC (OR = 0.72, 95% CI, 0.54-0.97). Never/occasional consumers of alcohol with the MTHFR rs1801133 CT/TT genotype were also at a reduced risk of CRC compared to never/occasional drinkers with the CC genotype (OR = 0.68, 95% CI, 0.47-0.98) (P for interaction = 0.27). The results indicate that the folate pathway is likely to be involved in alcohol-related CRC development.
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Effect of folic acid intervention on the change of serum folate level in hypertensive Chinese adults: do methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms affect therapeutic responses?
Qin, X, Li, J, Cui, Y, Liu, Z, Zhao, Z, Ge, J, Guan, D, Hu, J, Wang, Y, Zhang, F, et al
Pharmacogenetics and genomics. 2012;(6):421-8
Abstract
OBJECTIVES To assess the influence of individual methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase A2756G polymorphisms on the change of serum folate concentration in response to different dosages and durations of folic acid (FA) supplementation in hypertensive Chinese adults. METHODS A total of 480 patients with mild or moderate essential hypertension were randomly assigned to three treatment groups: (a) enalapril only (10 mg, control group); (b) enalapril FA tablet [10 : 0.4 mg (10 mg of enalapril combined with 0.4 mg of FA), low-FA group]; (c) enalapril FA tablet (10 : 0.8 mg, high-FA group), once daily for 8 weeks. Individual serum folate levels were measured at baseline, and at 4 and 8 weeks posttreatment. RESULTS After 4 or 8 weeks of treatment, increases in serum folate were seen across all genotypes and FA dosage groups. However, compared with patients with 677CC genotype, those with CT or TT genotype in the low-FA group and TT genotype in the high-FA group still had significantly lower folate concentrations, particularly women. In the low-FA group, patients with CT or TT genotype showed an attenuated response compared with those with CC genotype (median ratio of folate at week 8 to that at baseline: CC,1.953 vs. CT,1.755 or TT,1.637, P<0.01 for both). Such an attenuated response was not observed in the high-FA group. Yet, only in the high-FA group did serum folate appear to reach a plateau after 4 weeks of treatment in all three MTHFR 677 genotypes and the methionine synthase 2756 AG/GG genotype. CONCLUSION We demonstrated that MTHFR C677T polymorphisms can not only affect serum folate levels at the baseline and post-FA treatment, but also therapeutic responses to various dosages and durations of FA supplementation.
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Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials.
Holmes, MV, Newcombe, P, Hubacek, JA, Sofat, R, Ricketts, SL, Cooper, J, Breteler, MM, Bautista, LE, Sharma, P, Whittaker, JC, et al
Lancet (London, England). 2011;(9791):584-94
Abstract
BACKGROUND The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. METHODS We established a collaboration of genetic studies consisting of 237 datasets including 59,995 individuals with data for homocysteine and 20,885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45,549 individuals, 2314 stroke events, 269 transient ischaemic attacks). FINDINGS The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 μmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 μmol/L, -0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region. INTERPRETATION In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption. FUNDING Full funding sources listed at end of paper (see Acknowledgments).
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Effect of the MTHFR C677T and A1298C polymorphisms on survival in patients with advanced CKD and ESRD: a prospective study.
Jamison, RL, Shih, MC, Humphries, DE, Guarino, PD, Kaufman, JS, Goldfarb, DS, Warren, SR, Gaziano, JM, Lavori, P, ,
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2009;(5):779-89
Abstract
BACKGROUND Abnormalities in the gene regulating methylenetetrahydrofolate reductase (MTHFR) are associated with increased homocysteine levels and increased mortality in normal and chronic kidney disease (CKD) populations. STUDY DESIGN Gene association study. SETTING & PARTICIPANTS This was a substudy of 677 patients from 21 Veterans Affairs medical centers participating in a randomized clinical trial (Homocysteinemia in Kidney and End-Stage Renal Disease [HOST]) of the effect on all-cause mortality of vitamin-induced lowering of plasma homocysteine levels. Of 677 patients, 213 (31%) were treated by using dialysis (end-stage renal disease [ESRD]) and 464 (69%) had a Cockcroft-Gault estimated creatinine clearance less than 30 mL/min (advanced CKD). PREDICTOR Polymorphisms C677T (rs1801133) and A1298C (rs1801131) of the MTHFR gene. OUTCOMES Unadjusted and adjusted all-cause mortality. MEASUREMENTS DNA was extracted from blood samples and amplified by means of polymerase chain reaction. RESULTS The adjusted hazard ratio in a recessive model of the relationship between the C677T polymorphism and all-cause mortality in all patients was 1.47 (95% confidence interval, 1.00 to 2.16; P = 0.05). In patients with ESRD with the mutant TT genotype, the adjusted hazard ratio for mortality in all patients was 2.27 (95% confidence interval, 1.07 to 4.84; P = 0.03); patients with advanced CKD showed a similar, although not significant, trend. The risk of myocardial infarction (P = 0.05) and composite risk of myocardial infarction, stroke, lower-extremity amputation, and mortality (P = 0.02) were greater in patients with ESRD with the mutant T allele at nucleotide 677. The overall relationship between the A1298C polymorphism and mortality was not significant (P = 0.6). LIMITATIONS Participants were 98% men; DNA samples were not obtained at enrollment in HOST; linkage disequilibrium with another causal polymorphism is a potential confounding factor; and power was reduced by the limited number of participants. CONCLUSIONS These findings provide additional support for the hypothesis that the mutant TT genotype at nucleotide 677 of the gene regulating MTHFR activity may increase the mortality risk in patients with ESRD.