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1.
Associations between Serum Betaine, Methyl-Metabolizing Genetic Polymorphisms and Risk of Incident Type 2 Diabetes: A Prospective Cohort Study in Community-Dwelling Chinese Adults.
Lu, X, Huang, R, Li, S, Fang, A, Chen, Y, Chen, S, Wang, F, Lin, X, Liu, Z, Zhu, H
Nutrients. 2022;(2)
Abstract
Previous studies have explored associations between betaine and diabetes, but few have considered the effects of genes on them. We aimed to examine associations between serum betaine, methyl-metabolizing genetic polymorphisms and the risk of type 2 diabetes in Chinese adults. This prospective study comprised 1565 subjects aged 40-75 without type 2 diabetes at baseline. Serum betaine was measured by high-performance liquid chromatography tandem mass spectrometry. Genotyping of methyl-metabolizing genes was detected by Illumina ASA-750K arrays. Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During a median of 8.9 years of follow-up, 213 participants developed type 2 diabetes. Compared with participants in the lowest quartile of serum betaine, those in the highest quartile had lower risk of type 2 diabetes, adjusted HRs (95%CIs) was 0.46 (0.31, 0.69). For methylenetetrahydrofolate reductase (MTHFR) G1793A (rs2274976) and MTHFR A1298C (rs1801131), participants carrying 1793GA + AA and 1298AC + CC had lower risk of type 2 diabetes. Interactions of serum betaine and genotype of MTHFR G1793A and MTHFR A1298C could be found influencing type 2 diabetes risk. Our findings indicate that higher serum betaine, mutations of MTHFR G1793A and A1298C, as well as the joint effects of them, are associated with lower risk of type 2 diabetes.
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Influence of Folate-Related Gene Polymorphisms on High-Dose Methotrexate-Related Toxicity and Prognosis in Turkish Children with Acute Lymphoblastic Leukemia.
Yazıcıoğlu, B, Kaya, Z, Güntekin Ergun, S, Perçin, F, Koçak, Ü, Yenicesu, İ, Gürsel, T
Turkish journal of haematology : official journal of Turkish Society of Haematology. 2017;(2):143-150
Abstract
OBJECTIVE High-dose methotrexate (HD-MTX) is widely used in the consolidation phase of childhood acute lymphoblastic leukemia (ALL), but the roles that polymorphisms in folate-related genes (FRGs) play in HD-MTX toxicity and prognosis in children with ALL are not understood. The aims of this study were to investigate the frequencies of polymorphisms in the genes for thymidylate synthase (TS), methionine synthase reductase (MTRR), and methylene tetrahydrofolate reductase (MTHFR) in Turkish children with ALL and to assess associations between these polymorphisms and HD-MTX-related toxicity and leukemia prognosis in this patient group. MATERIALS AND METHODS FRG polymorphisms were assessed by real-time polymerase chain reaction. Survival status, MTX levels, and toxicity data were retrieved from 106 patients' charts. RESULTS The allele frequencies for the FRG polymorphisms were as follows: TS 2R 41.0%, 3R 57.0%, and 4R 2.0%; MTRR 66A 42.4% and 66G 57.6%; MTHFR 677C 59.3% and 677T 40.7%; and MTHFR 1298A 58.1% and 1298C 41.9%. At the 48th hour of HD-MTX infusion, serum MTX was significantly higher in patients who had TS 2R/3R/4R variants as compared to those with wild-type TS (p<0.05). No significant differences were detected with respect to event-free survival or toxicity between wild-type and other FRG variants. CONCLUSION The frequencies of FRG polymorphisms in Turkish children with ALL are similar to those reported in other Caucasian populations. This is the first published finding of the TS 3R/4R variant in the Turkish population. The results indicate that HD-MTX can be tolerated by leukemic children with some polymorphic variants of FRG; thus, it may prevent future risk of leukemic relapse.
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3.
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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4.
Homocysteine and all-cause mortality in hypertensive adults without pre-existing cardiovascular conditions: Effect modification by MTHFR C677T polymorphism.
Xu, B, Kong, X, Xu, R, Song, Y, Liu, L, Zhou, Z, Gu, R, Shi, X, Zhao, M, Huang, X, et al
Medicine. 2017;(8):e5862
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Abstract
BACKGROUND Previous studies support an association between elevated total homocysteine (tHcy) levels and increased all-cause mortality. However, few prospective studies have examined this association in hypertensive patients, and/or tested any effect modification by the methylene tetrahydrofolate reductase (MTHFR) C677T genotype. METHODS This was a post hoc analysis of the China Stroke Primary Prevention Trial. Serum tHcy and folate were measured at baseline. Individual MTHFR C677T genotype (CC, CT, and TT) was determined. Evidence for death included death certificates or home visits. Cumulative hazards of all-cause mortality by tHcy quartiles were estimated using the Kaplan-Meier method, and group differences were compared by log-rank tests. Hazard ratios (HRs) and 95% confidence intervals were estimated by Cox proportional-hazard regression models, adjusting for age, sex, baseline folate, vitamin B12, blood pressure, body mass index, smoking and alcohol drinking status, study center, total cholesterol, triglycerides, high-density lipoprotein cholesterol, fasting glucose, creatinine, and treatment group. Potential effect modification by the MTHFR genotype on the relationship between tHcy and all-cause mortality was tested. RESULTS The analyses included 20,424 hypertensive patients (41% males) without a history of myocardial infarction or stroke. Baseline mean age (SD) was 60 ± 7.5 years and mean (SD) serum tHcy was 14.5 ± 8.4 μmol/L. After a mean follow-up period of 4.5 years, there were 612 (3%) all-cause deaths. Kaplan-Meier survival curves revealed a graded relationship between tHcy quartiles and all-cause mortality. The HRs, using the lowest quartile as the reference, were 1.2, 1.2, and 1.5 in Q2, Q3, and Q4, respectively. A linear trend test, using natural log-transformed tHcy, resulted in an HR of 1.5 (95% confidence interval 1.2-1.9, P < .001) after adjustment for lifestyle and health-related variables. Whereas the MTHFR genotype alone had little effect on mortality, it significantly modified the tHcy-mortality association, which was much stronger in the CC/CT genotype than in the TT genotype (P for interaction < 0.05). CONCLUSIONS Among Chinese hypertensive patients without cardiovascular comorbidities, elevated tHcy was a significant risk marker for death from all causes, and the association was subject to effect modification by MTHFR genotypes. If confirmed that tHcy and MTHFR genotypes may serve as useful biomarkers for mortality risk assessment and targeted intervention.
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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 the MTHFR 677C/T polymorphism on homocysteinemia in response to creatine supplementation: a case study.
Petr, M, Steffl, M, Kohlíková, E
Physiological research. 2013;(6):721-9
Abstract
Creatine (Cr) is recommended as a dietary supplement especially for athletes but its therapeutic potential is also discussed. It is assumed that human body uses Cr for the formation of phosphocreatine, which is necessary for muscular work as a source of energy. Production of Cr in a body is closely connected to methionine cycle where guanidinoacetate (GAA) is in a final step methylated from S-adenosylmethionine (SAM). Increased availability of SAM for phosphatidylcholine (PC) and sarcosine synthesis can potentially stimulate endogenous production of betaine a thus methylation of homocysteine (HCy) to form methionine. Our subject who was methylenetetrahydrofolate reductase (MTHFR) 677TT homozygote lowered plasma HCy from 33.3 micromol/l to 17.1 micromol/l following one-month Cr supplementation (5 g/day) opposite to 677CC and CT genotypes whose HCy levels tended to increase (but still in normal ranges). We suppose that Cr supplementation stimulates pathways leading to production of sarcosine which can serve to regenerate tetrahydrofolate (THF) to form 5,10-methylene-THF. This could potentially increase MTHFR enzyme activity which may later result in increased HCy methylation. Cr supplementation significantly effects metabolism of one carbon unit and potentially lower body´s demands for methyl groups. This could be beneficial as in the case of reduced enzyme activity such as MTHFR 677C/T polymorphism.
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Evaluation of ABO blood groups as a risk factor for myocardial infarction.
Jukic, I, Bingulac-Popovic, J, Dogic, V, Hecimovic, A, Babic, I, Batarilo, I, Maglov, C, Sturm, D
Blood transfusion = Trasfusione del sangue. 2013;(3):464-5
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Prevalence of inherited thrombophilia in patients with documented stent thrombosis.
Zavalloni, D, Presbitero, P, Lodigiani, C, Mango, R, Cogliati, T, Quaglia, I, Corrada, E, Mendolicchio, GL, Gasparini, GL, Rossi, ML, et al
Circulation journal : official journal of the Japanese Circulation Society. 2012;(8):1874-9
Abstract
BACKGROUND Stent thrombosis (ST) is a multi-factorial process involving different mechanisms. The impact of inherited coagulation disorders in the genesis of ST has never been assessed. The aim of the present study was to evaluate the prevalence of G1691A Factor V Leiden mutation, G20210A Factor II (prothrombin) mutation and C677T homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism in patients with ST. METHODS AND RESULTS The prevalence of the aforementioned gene variations was assessed in 127 patients: 50 admitted for ST and 77 previously treated with percutaneous coronary intervention not developing ST. A control cohort of 529 healthy volunteers was sampled from the same geographical area. Patients with ST were carriers of at least 1 gene variation in 28% of cases. The prevalence of G1691A Factor V Leiden mutation (odds ratio [OR]=0.64; 95% confidence interval [CI]: 0.04-10.5), G20210A Factor II mutation (OR=0.63; 95% CI: 0.12-3.28) and C677T MTHFR homozygous polymorphism (OR=1.13; 95% CI: 0.47-2.72) did not differ significantly among patients with or without ST. The logistic regression model did not show a significant association between gene variations and ST (OR=0.61; 95% CI: 0.24-1.60; P=0.32). CONCLUSIONS A specific association between studied gene variations and ST has not been detected. The relatively high prevalence of at least 1 gene anomaly in such a rare subset of patients, and its consequences in term of secondary prevention therapy, suggests that screening for thrombophilia might be justifiable in cases of ST.
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C677T methylenetetrahydrofolate reductase polymorphism interferes with the effects of folic acid and zinc sulfate on sperm concentration.
Ebisch, IM, van Heerde, WL, Thomas, CM, van der Put, N, Wong, WY, Steegers-Theunissen, RP
Fertility and sterility. 2003;(5):1190-4
Abstract
OBJECTIVE To determine the frequency of C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism in fertile and subfertile males, and the MTHFR-dependent response of sperm concentration after folic acid and/or zinc sulfate intervention. DESIGN Double-blind, placebo-controlled intervention study. Two outpatient fertility clinics and nine midwifery practices in The Netherlands. PATIENT(S): One hundred thirteen fertile and 77 subfertile males. Daily capsules of folic acid (5 mg) and/or zinc sulfate (66 mg), or placebo for 26 weeks. MAIN OUTCOME MEASURE(S): Prevalence of C677T MTHFR polymorphism and the response of sperm concentration related to MTHFR carriership after intervention treatment. RESULT(S): The C677T methylenetetrahydrofolate reductase genotypes were comparable in fertile and subfertile males. Independent of fertility state, sperm concentration significantly increased in wild-types after folic acid and zinc sulfate treatment only. Heterozygotes and homozygotes did not significantly benefit from either treatment. CONCLUSION(S): C677T methylenetetrahydrofolate reductase polymorphism is not a risk factor for male factor subfertility. In contrast to heterozygotes and homozygotes for C677T MTHFR polymorphism, sperm concentration in wild-types significantly improved after folic acid and zinc sulfate intervention. A stronger role of other folate genes on spermatogenesis is suggested.