Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism

Fredriksen, Åse; Meyer, Klaus; Ueland, Per Magne; Vollset, Stein Emil; Grotmol, Tom; Schneede, Jörn

doi:10.1002/humu.20522

Cited by 159 publications

(139 citation statements)

References 77 publications

(67 reference statements)

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“…Previously published data show that the TCN2 776 G allele is associated with decreased transcription and decreased concentrations of cellular and plasma transcobalamin, the carrier protein that delivers vitamin B 12 to cells [36]. This suggests [36][37][38] in addition to increased MMA [39] and Hcy concentrations [37,40]. Previous studies, however, did not find an association between this polymorphism and either holotranscolbalamin [41] or Hcy [38,42].…”

Section: Discussionmentioning

confidence: 95%

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

et al. 2012

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Individuals with Down syndrome (DS) carry three copies of the Cystathionine b-synthase (CbS) gene. The increase in the dosage of this gene results in an altered profile of metabolites involved in the folate pathway, including reduced homocysteine (Hcy), methionine, S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM). Furthermore, previous studies in individuals with DS have shown that genetic variants in genes involved in the folate pathway influence the concentrations of this metabolism's products. The purpose of this study is to investigate whether polymorphisms in genes involved in folate metabolism affect the plasma concentrations of Hcy and methylmalonic acid (MMA) along with the concentration of serum folate in individuals with DS. Twelve genetic polymorphisms were investigated in 90 individuals with DS (median age 1.29 years, range 0.07-30.35 years; 49 male and 41 female). Genotyping for the polymorphisms was performed either by polymerase chain reaction (PCR) based techniques or by direct sequencing. Plasma concentrations of Hcy and MMA were measured by liquid chromatography-tandem mass spectrometry as previously described, and serum folate was quantified using a competitive immunoassay. Our results indicate that the MTHFR C677T, MTR A2756G, TC2 C776G and BHMT G742A polymorphisms along with MMA concentration are predictors of Hcy concentration. They also show that age and Hcy concentration are predictors of MMA concentration. These findings could help to understand how genetic variation impacts folate metabolism and what metabolic consequences these variants have in individuals with trisomy 21.

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Section: Discussionmentioning

confidence: 95%

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

et al. 2012

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“…Dekou et al 10 and Fredriksen et al 15 have both reported that CBS 844ins68 carriers have fasting homocysteine levels that are modestly but significantly lower than those of noncarriers, although others have found no statistically significant difference in homocysteine levels between carriers and noncarriers. 16 -19 Interestingly, some studies in which carrier status did not influence fasting homocysteine found that after methionine loading, used experimentally to raise homocysteine concentrations and induce the CBS-mediated transsulfuration pathway, the CBS 844ins68 allele is associated with decreased homocysteine levels.…”

Section: Discussionmentioning

confidence: 99%

“…20 Others have reported effects attributable to the 699C4T and 1080C4T polymorphisms; however, these are both silent changes that themselves are unlikely to have a direct effect indicating the possibility of linkage disequilibrium with as yet unknown transcriptional control elements. 15,23 Two reports, a European-wide study 9 and a subsequent study from the United Kingdom, 10 have suggested that the CBS 844ins68 allele may counterbalance the homocysteine-raising effect of the MTHFR 677TT genotype, although these findings were not replicated in a subsequent UK study. 19 Our results, derived from a Northern Irish sample, support the reports that homocysteine levels in MTHFR 677TT homozygotes who carry the CBS 844ins68 Figure 2 Median serum folate levels by cystathionine b-synthase (CBS) 844ins68 genotype within each 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C4T genotype class.…”

Section: Discussionmentioning

confidence: 99%

Influence of the cystathionine β-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations

et al. 2008

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A high homocysteine, low folate phenotype is a feature of many diseases. The effect of the cystathionine b-synthase (CBS) 844ins68 polymorphism on homocysteine and folate concentrations was examined alone and in the context of the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C4T polymorphism in a Northwestern European male population. The MTHFR 677TT genotype is known to be associated with increased homocysteine and decreased folate relative to CT heterozygotes and CC homozygotes in this and other populations. MTHFR 677TT homozygotes who were also CBS 844ins68 carriers had homocysteine and folate concentrations similar to those of individuals with the MTHFR 677CT and CC genotypes. Homocysteine levels in MTHFR 677TT subjects carrying the CBS 844ins68 allele were 24.1% lower than in non-carriers (6.66 vs 8.77 lmol/l, P ¼ 0.045), and serum folate levels were 27.7% higher (11.16 vs 8.74 nmol/l, P ¼ 0.034). These findings suggest that the CBS 844ins68 allele 'normalizes' homocysteine and folate levels in MTHFR 677TT individuals.

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“…Significantly, the two MTHFR mutant homozygotes (TTCC) never occur together, which appears to be the situation globally, as large scale studies by Fredriksen et al (2007) in Norway and a meta-analysis by Martinez-frias (2008) also fail to get this combination. It is reasonable to conclude that this genotypic combination is under strong selection pressure (also see Callejon et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Association of MTHFR and RFC1 gene polymorphism with hyperhomocysteinemia and its modulation by vitamin B12 and folic acid in an Indian population

Sukla

Raman

2011

Eur J Clin Nutr

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Background/Objectives: Unlike most Western populations, MTHFR 677T is a rare allele and a risk factor for a variety of disorders in India. What kind of nutritional (environmental) and/or genetic factors could contribute to the genetic risk is not known. To assess the incidence of hyperhomocysteinemia and its correlation with the polymorphism in homocysteine (Hcy)-pathway genes and associated cofactors in the native populations of eastern India. Subjects/Methods: Healthy population from four eastern states of India. Genotyping of SNPs, HPLC and chemiluminescencebased assay for homocysteine, vitamin B12 and folic acid.Results: Approximately 30% of the population has hyperhomocysteinemia (415 mmol/lit; hypHcy) with varying frequencies in the four states from where samples were collected (n ¼ 1426). Polymorphisms of MTR and CBS do not affect hypHcy. 677T and 1298C alleles of MTHFR and G80 RFC-1 show association with hypHcy. In contrast, RFC-1 80AA is protective even in presence of 677T MTHFR. Addition of each mutant allele has an additive effect on Hcy level. Vitamin B12 (cofactor in methionine synthesis) clearly modulates the genotypic effect on Hcy level. Although frequency of individuals with low folic acid is B11, 49% of the population is vitamin B12 deficient (o220 pg/lit) and has a significant negative correlation with Hcy. Individuals with optimum vitamin B12 and folic acid generally have low Hcy, even in risk genotypes. Conclusions: One of the plausible reasons for susceptibility of individuals with MTHFR C677T in the studied population to various disorders is the high frequency of hyperhomocysteinemia and vitamin B12 deficiency in the 'healthy population'. Apparently, supplementation of vitamin B 12 to this health-impoverished community may help lessen the risk of several multifactorial disorders.

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Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism

Cited by 159 publications

References 77 publications

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

Influence of the cystathionine β-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations

Association of MTHFR and RFC1 gene polymorphism with hyperhomocysteinemia and its modulation by vitamin B12 and folic acid in an Indian population

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