Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2483-2488 ◽  
Author(s):  
Leo A. J. Kluijtmans ◽  
Ian S. Young ◽  
Colin A. Boreham ◽  
Liam Murray ◽  
Dorothy McMaster ◽  
...  
Keyword(s):  
Young Adults ◽  
Vitamin B12 ◽  
Methylenetetrahydrofolate Reductase ◽  
Dietary Factors ◽  
Methionine Synthase ◽  
Interactive Effects ◽  
Serum Folate ◽  
Homocysteine Concentration ◽  
Functional Polymorphisms ◽  
Methionine Synthase Reductase

A modestly elevated total plasma homocysteine concentration (tHcy) is generally accepted as an independent and graded risk factor for various pathologies, including vascular diseases, neural tube defects, Alzheimer disease, and pregnancy complications. We analyzed 5 common functional polymorphisms in enzymes involved in homocysteine metabolism (ie, methylenetetrahydrofolate reductase [MTHFR] 677C>T and 1298A>C, methionine synthase [MTR] 2756A>G, cystathionine β-synthase [CBS] 844ins68, and methionine synthase reductase [MTRR] 66A>G) in 452 young adults, and quantified their independent and interactive effects on tHcy concentrations. Serum folate, red cell folate, vitamin B12, and tHcy concentrations were significantly influenced by MTHFR 677C>T genotypes. A particularly strong interaction was observed between theMTHFR 677TT genotype and serum folate, which led to a high tHcy phenotype that was more pronounced in males. The genetic contribution to the variance in tHcy was estimated to be approximately 9%, compared with approximately 35% that could be attributed to low folate and vitamin B12. Our study indicates that dietary factors are centrally important in the control of tHcy levels in young adults with additional, but somewhat weaker, genetic effects. These data underscore the potential benefits that may be gained by improving the dietary status of young adults, and provide support for the implementation of folate/B-vitamin food fortification programs.

Association of homocysteine (but not of MTHFR 677 C>T, MTR 2756 A>G, MTRR 66 A>G and TCN2 776 C>G) with ischaemic cerebrovascular disease in Sicily

2006 ◽  
Vol 96 (08) ◽  
pp. 154-159 ◽  
Author(s):  
Rosa-Maria Guéant-Rodriguez ◽  
Guido Anello ◽  
Rosario Spada ◽  
Antonino Romano ◽  
Adrian Fajardo ◽  
...  
Keyword(s):  
Cerebrovascular Disease ◽  
Vitamin B12 ◽  
Methylenetetrahydrofolate Reductase ◽  
Methionine Synthase ◽  
Italian Population ◽  
Significant Independent Predictor ◽  
Methionine Synthase Reductase ◽  
Ischaemic Cerebrovascular Disease ◽  
Folate And Vitamin B12 ◽  
Neutral Effect

SummaryAssociation between methylenetetrahydrofolate reductase polymorphism (MTHFR 677 C>T), a determinant of homocysteine plasma level (t-Hcys), with ischaemc cerebrovascular disease (iCVD) seems to be neutral in North Europe and North America. The association of 2756 A>G of methionine synthase (MTR), 66 A>G of methionine synthase reductase (MTRR) and 776 C>G of transcobalamin (TCN2) needs to be evaluated further. It was the objective of this study to evaluate the association of these polymorphisms, t-Hcys, vitamin B12 and folate levels with iCVD, in an Italian population from Sicily. We investigated the association of these polymorphisms, t-Hcys, vitamin B12 and folate with iCVD in 252 subjects, including 131 cases and 121 sexand agematched healthy controls. t-Hcys was higher in the iCVD group than in controls [15.3 (11.5–17.9) vs. 11.6 (9.4–14.5) µM; P=0. 0007] and also in subjects withTCN2 776CG genotype, compared to homozygous genotypes [13.5 (9.9± 16.9) vs. 11.7 (9.6 ± 14.4) µM; P=0. 0327]. The folate level in cases and controls was consistent with an adequate dietary intake [12.7 (9.0–15.3) vs. 12.5 (9.6–16.9) nM; P=0. 7203]. In multivariate analysis, t-Hcys was a significant independent predictor of iCVD with an odds ratio of 1.14 (95% C.I. : 1.06–1.24; P=0. 0006). No association was found between MTHFR, MTR, MTRR and TCN2 polymorphisms and iCVD risk. We have found an influence of t-Hcys and a neutral effect of MTHFR, MTR, MTRR and TCN2 on iCVD risk in Sicily. The neutral influence of these polymorphisms may be explained by adequate status in folate and vitamin B12. Other factors underlying the increased t-Hcys need further investigations.

scholarly journals Functional Polymorphisms of Folate-Metabolizing Enzymes in Relation to Homocysteine Concentrations in Systemic Lupus Erythematosus

2008 ◽  
Vol 35 (11) ◽  
pp. 2179-2186 ◽  
Author(s):  
CAROLYN M. SUMMERS ◽  
ANDREW J. CUCCHIARA ◽  
ELENI NACKOS ◽  
ANDREA L. HAMMONS ◽  
ELISABETH MOHR ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
African American ◽  
Lupus Erythematosus ◽  
Methylenetetrahydrofolate Reductase ◽  
Methionine Synthase ◽  
Systemic Lupus ◽  
Metabolizing Enzymes ◽  
Functional Polymorphisms ◽  
Methionine Synthase Reductase ◽  
Caucasian Patients

ObjectiveTo determine if functional polymorphisms of folate/homocysteine pathway enzymes are associated with homocysteine concentrations and/or coronary artery calcification (CAC) scores in patients with systemic lupus erythematosus (SLE) and controls.MethodsWe investigated 163 SLE patients and 160 controls. Functional polymorphisms in 6 genes in the folate/homocysteine pathway were genotyped: 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, cystathionine β-synthase (CBS) 844ins68, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G, thymidylate synthase (TYMS) 1494del6, and dihydrofolate reductase (DHFR) c.86+60_78.ResultsHomocysteine levels were higher in African American SLE patients than Caucasian patients and African American controls. Genotype distributions were significantly different in African American and Caucasian controls for 6 of the 7 polymorphisms. Genotype distributions for each polymorphism did not differ significantly between SLE patients and controls even after stratification by race. Glomerular filtration rate was strongly negatively correlated to homocysteine levels, and was therefore adjusted for as a covariate in the models of the effects of the polymorphisms on homocysteine levels. In SLE patients none of the 7 polymorphisms was associated with homocysteine concentrations. In Caucasian controls only MTHFR 677C>T and 1298A>C showed effects on homocysteine similar to what would be expected from the literature. There were no genotypic associations with median CAC scores in SLE patients or controls with and without stratification by race.ConclusionPolymorphisms in folate/homocysteine metabolizing enzymes do not predict higher homocysteine levels or CAC scores in patients with SLE.

scholarly journals Haplotype analysis of the folate-related genes MTHFR, MTRR, and MTR and migraine with aura

Cephalalgia ◽  
2013 ◽  
Vol 33 (7) ◽  
pp. 469-482 ◽  
Author(s):  
Kathryn A Roecklein ◽  
Ann I Scher ◽  
Albert Smith ◽  
Tamara Harris ◽  
Gudny Eiriksdottir ◽  
...  
Keyword(s):  
Migraine With Aura ◽  
Multiple Testing ◽  
Haplotype Analysis ◽  
Methylenetetrahydrofolate Reductase ◽  
Population Based ◽  
Methionine Synthase ◽  
Association Testing ◽  
Methionine Synthase Reductase ◽  
Increased Risk ◽  
Genes Encoding

Aims The C677T variant in the methylenetetrahydrofolate reductase ( MTHFR; EC 1.5.1.20) enzyme, a key player in the folate metabolic pathway, has been associated with increased risk of migraine with aura. Other genes encoding molecular components of this pathway include methionine synthase ( MTR; EC 2.1.1.13) and methionine synthase reductase ( MTRR; EC 2.1.1.135) among others. We performed a haplotype analysis of migraine risk and MTHFR, MTR, and MTRR. Methods Study participants are from a random sub-sample participating in the population-based AGES-Reykjavik Study, including subjects with non-migraine headache ( n = 367), migraine without aura ( n = 85), migraine with aura ( n = 167), and no headache ( n = 1347). Haplotypes spanning each gene were constructed using Haploview. Association testing was performed on single SNP and haplotypes using logistic regression, controlling for demographic and cardiovascular risk factors and correcting for multiple testing. Results Haplotype analysis suggested an association between MTRR haplotypes and reduced risk of migraine with aura. All other associations were not significant after correcting for multiple testing. Conclusions These results suggest that MTRR variants may protect against migraine with aura in an older population.

Effects of Methionine Synthase (MS) A2756G and Methionine Synthase Reductase (MSR) A66G Polymorphisms on Methionine Metabolism in Brazilian Pregnant Women and Their Neonates.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3686-3686
Author(s):  
Patricia R. Barbosa ◽  
Sally P. Stabler ◽  
Mario H. Hirata ◽  
Rosario D.C. Hirata ◽  
Robert H. Allen ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Confidence Intervals ◽  
T Test ◽  
Methionine Synthase ◽  
Serum Folate ◽  
Geometric Means ◽  
Methionine Synthase Reductase ◽  
Pcr Rflp ◽  
Total Homocysteine ◽  
Ms A2756g

Abstract Methionine synthase (MS) is a cobalamin dependent enzyme that catalyses the remethylation of homocysteine to methionine. The methionine synthase reductase (MSR) maintains adequate levels of methylcob(III)alamin, the activated cofactor for MS. The aim of this study was to investigate the effect of MS A2756G and MSR A66G polymorphisms on total homocysteine (tHcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) levels in 390 pregnant women and their 292 newborns, from Sorocaba city, Brazil. Genotypes of two polymorphisms were determined by PCR-RFLP. Pregnant women with MS 2756AA genotype have higher tHcy and lower Cbl levels than those with 2756G alleles. The MMA values were increased in neonates with MS 2756AA genotypes (Table 1). There are no difference between the maternal values of Cbl, serum folate, tHcy, MMA and SAM according to MSR A66G genotypes.The values of SAM were lower in neonates with MSR 66G alleles than those with AA genotypes (Table 2). We conclude that MS 2756AA genotypes are associated with higher tHcy levels in pregnant women and higher MMA levels in neonates. The MSR 66GG genotypes is associated with lower SAM levels in neonates. Table 1- Distribution of geometric means and confidence intervals 95% (CI 95%) and numbers of subjects for maternal and neonatal values of cobalamin (Cbl), serum folate, total homocysteine (tHcy), methymalonic acid (MMA) and S- adenosylmethionine (SAM) according to genotypes for the polymorphism MS A2756G. Variables Genotypes for MS A2756G Student t Test AA AG + GG Pregnant Women Cbl (pmol/L) 139 (133 – 144) 235 156 (146 – 166) 129 P= 0.001 SF (nmol/L) 14.3 (13.6 – 15.0) 234 14.5 (13.6 – 15.5) 129 P= 0.667 tHcy( μmol/L) 6.8 (6.5 – 7.1) 235 6.2 (5.9 – 6.6) 128 P= 0.036 MMA(nmol/L) 234 (219 – 245) 194 241 (219 – 265) 106 P= 0.610 SAM(nmol/L) 81.8 (77.9 – 86,0) 229 83.1 (79.1 – 87.4) 124 P= 0.663 Neonates Cbl (pmol/L) 227 (212 – 244) 188 234 (213 – 257) 101 P= 0.646 SF (nmol/L) 32.0 (31.0 – 33.0) 186 32.0 (30.8 – 33.2) 99 P= 0.967 tHcy μmol/L) 5.8 (5.5 – 6.1) 185 5.5 (5.1 – 5.9) 100 P= 0.229 MMA(nmol/L) 383 (364 – 402) 183 342 (317 – 369) 100 P= 0.011 SAM(nmol/L) 188 (181 – 196) 178 182 (168 – 197) 98 P= 0.491 Table 2 - Distribution of geometric means and confidence intervals 95% (CI (%%) and number of subjects for neonatal values of cobalamin (Cbl), serum folate, total homocysteine (tHcy), methylmalonic acid (MMA) and S- adenosylmethionine (SAM) according to genotypes for the polymorphism MSR A66G. Variables Genotypes MSR A66G Student t Test AA AG GG Groups not sharing a common superscript letter are significantly different at P<0.05 based on Tukey’s test Neonates Cbl (pmol/L) 225 (202 – 249) 86 229 (214 – 246) 166 247 (205 – 298) 35 P= 0.602 SF (nmol/L) 33.0 (31.6 – 34.4) 84 31.7 (30.7 – 32.7) 166 31.8 (29.7 – 34.2) 33 P= 0.352 tHcy μmol/L) ( 5.7 (5.3 – 6.2) 84 5.6 (5.3 – 5.9) 165 5.9 (5.3 – 6.6) 34 P= 0.618 MMA (nmol/L) 360 (334 – 389) 84 378 (357 – 400) 163 339 (299 – 384) 34 P= 0.230 SAM (nmol/L) 200 (186 – 215)a 82 184 (176 – 192)a 159 170 (149 – 195)b 33 P= 0.032

Genetic polymorphisms of the enzymes involved in DNA methylation and synthesis in elite athletes

2011 ◽  
Vol 43 (16) ◽  
pp. 965-973 ◽  
Author(s):  
Ileana Terruzzi ◽  
Pamela Senesi ◽  
Anna Montesano ◽  
Antonio La Torre ◽  
Giampietro Alberti ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Polymorphisms ◽  
Methylenetetrahydrofolate Reductase ◽  
Late Phase ◽  
Muscle Growth ◽  
Methionine Synthase ◽  
Control Group ◽  
Dna Hypomethylation ◽  
Methionine Synthase Reductase ◽  
Proliferation And Differentiation

Physical exercise induces adaptive changes leading to a muscle phenotype with enhanced performance. We first investigated whether genetic polymorphisms altering enzymes involved in DNA methylation, probably responsible of DNA methylation deficiency, are present in athletes' DNA. We determined the polymorphic variants C667T/A1298C of 5,10-methylenetetrahydrofolate reductase (MTHFR), A2756G of methionine synthase (MTR), A66G of methionine synthase reductase (MTRR), G742A of betaine:homocysteine methyltransferase (BHMT), and 68-bp ins of cystathionine β-synthase (CBS) genes in 77 athletes and 54 control subjects. The frequency of MTHFR (AC), MTR (AG), and MTRR (AG) heterozygous genotypes was found statistically different in the athletes compared with the control group ( P = 0.0001, P = 0.018, and P = 0.0001), suggesting a reduced DNA methylating capacity. We therefore assessed whether DNA hypomethylation might increase the expression of myogenic proteins expressed during early (Myf-5 and MyoD), intermediate (Myf-6), and late-phase (MHC) of myogenesis in a cellular model of hypomethylated or unhypomethylated C2C12 myoblasts. Myogenic proteins are largely induced in hypomethylated cells [fold change (FC) = Myf-5: 1.21, 1.35; MyoD: 0.9, 1.47; Myf-6: 1.39, 1.66; MHC: 1.35, 3.10 in GMA, DMA, respectively] compared with the control groups (FC = Myf-5: 1.0, 1.38; MyoD: 1.0, 1.14; Myf-6: 1.0, 1.44; MHC: 1.0, 2.20 in GM, DM, respectively). Diameters and length of hypomethylated myotubes were greater then their respective controls. Our findings suggest that DNA hypomethylation due to lesser efficiency of polymorphic MTHFR, MS, and MSR enzymes induces the activation of factors determining proliferation and differentiation of myoblasts promoting muscle growth and increase of muscle mass.

scholarly journals The roles of MTRR and MTHFR gene polymorphisms in congenital heart diseases: a meta-analysis

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Aiping Xu ◽  
Weiping Wang ◽  
Xiaolei Jiang
Keyword(s):  
Gene Polymorphisms ◽  
Congenital Heart ◽  
Methylenetetrahydrofolate Reductase ◽  
Heart Diseases ◽  
Meta Analysis ◽  
Mthfr Gene ◽  
Methionine Synthase ◽  
Congenital Heart Diseases ◽  
Methionine Synthase Reductase ◽  
Study Participants

Background: We performed the present study to better elucidate the correlations of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms with the risk of congenital heart diseases (CHD). Methods: Eligible articles were searched in PubMed, Medline, Embase and CNKI. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations of MTHFR and MTRR gene polymorphisms with CHD. Results: A total of 47 eligible studies were finally included in our meta-analysis. Our overall analyses suggested that MTRR rs1801394, MTRR rs1532268, MTHFR rs1801131 and MTHFR rs1801133 polymorphisms were all significantly associated with the risk of CHD in certain genetic models. Further subgroup analyses according to ethnicity of study participants demonstrated that the MTRR rs1801394 polymorphism was significantly correlated with the risk of CHD only in Asians, whereas MTRR rs1532268, MTHFR rs1801133 and MTHFR rs1801131 polymorphisms were significantly correlated with the risk of CHD in both Asians and Caucasians. Conclusions: Our findings indicated that MTRR rs1532268, MTHFR rs1801131 and MTHFR rs1801133 polymorphisms may affect the risk of CHD in Asians and Caucasians, while the MTRR rs1801394 polymorphism may only affect in risk of CHD in Asians.

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