The 2756A&gt;G variant in the gene encoding methionine synthase: its relation with plasma homocysteine levels and risk of coronary heart disease in a Dutch case-control study

Klerk, Mariska; Lievers, Karin J.A; Kluijtmans, Leo A. J.; Blom, Henk J.; Heijer, Martin den; Schouten, Evert G.; Kok, F.J.; Verhoef, Petra

doi:10.1016/s0049-3848(03)00341-4

Cited by 61 publications

(40 citation statements)

References 28 publications

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“…However, other studies did not observe any association between this polymorphism and alterations in Hcy concentrations (15,16).…”

Section: Introduction Introduction Introduction Introduction Introducmentioning

confidence: 72%

“…This polymorphism has been investigated as a risk factor for some diseases, such as vascular disease, neural tube defects, coronary artery disease and DS, and the evaluation of its influence on Hcy concentrations becomes of great interest. However, most of the studies did not find any relationship between this polymorphism and alterations in Hcy concentrations (15,16), and the few studies that observed this relationship are contradictory with regard to the allele involved. Harmon et al (12) analyzed the relationship between MTR A2756G genotype and Hcy concentration in a cohort of 625 working men aged 30-49 years and presented evidence that the MTR 2756AA genotype was associated with a modest increase in plasma Hcy concentrations.…”

Section: Discussion Discussion Discussion Discussion Discussionmentioning

confidence: 93%

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The MTR A2756G polymorphism is associated with an increase of plasma homocysteine concentration in Brazilian individuals with Down syndrome

Biselli

Goloni-Bertollo

Haddad

et al. 2007

Braz J Med Biol Res

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Individuals with Down syndrome (DS) present decreased homocysteine (Hcy) concentration, reflecting a functional folate deficiency secondary to overexpression of the cystathionine ß-synthase gene. Since plasma Hcy may be influenced by genetic polymorphisms, we evaluated the influence of C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR), of A2756G polymorphism in the methionine synthase gene (MTR), and of A80G polymorphism in the reduced folate carrier 1 gene on Hcy concentrations in Brazilian DS patients. Fifty-six individuals with free trisomy 21 were included in the study. Plasma Hcy concentrations were measured by liquid chromatography-tandem mass spectrometry with linear regression coefficient r 2 = 0.9996, average recovery between 92.3 to 108.3% and quantification limits of 1.0 µmol/L. Hcy concentrations >15 µmol/L were considered to characterize hyperhomocystinemia. Genotyping for the polymorphisms was carried out by polymerase chain reaction followed by enzyme digestion and allele-specific polymerase chain reaction. The mean Hcy concentration was 5.2 ± 3.3 µmol/L. There was no correlation between Hcy concentrations and age, gender or MTHFR C677T, A1298C and reduced folate carrier 1 A80G genotype. However, Hcy concentrations were significantly increased in the MTR 2756AG heterozygous genotype compared to the MTR 2756AA wild-type genotype. The present results suggest that the heterozygous genotype MTR 2756AG is associated with the increase in plasma Hcy concentrations in this group of Brazilian patients with DS.

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“…However, other studies did not observe any association between this polymorphism and alterations in Hcy concentrations (15,16).…”

Section: Introduction Introduction Introduction Introduction Introducmentioning

confidence: 72%

Section: Discussion Discussion Discussion Discussion Discussionmentioning

confidence: 93%

The MTR A2756G polymorphism is associated with an increase of plasma homocysteine concentration in Brazilian individuals with Down syndrome

Biselli

Goloni-Bertollo

Haddad

et al. 2007

Braz J Med Biol Res

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“…Because the MS A2756G polymorphism is located in a potentially functional domain of the enzyme 44) , it has been hypothesized that this polymorphism may increase Hcy levels. However, previous studies have demonstrated that the MS A2756G polymorphism was not associated with Hcy levels 29,45) . Furthermore, although we observed that the GG genotype was negatively associated with arterial stiffness in our logistic analysis, this finding may be due to random error, given the limited number of subjects with the GG genotype.…”

Section: Discussionmentioning

confidence: 89%

Positive Association of Plasma Homocysteine Levels with Cardio-Ankle Vascular Index in a Prospective Study of Japanese Men from the General Population

Mantjoro

Toyota

Kanouchi

et al. 2016

JAT

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Aim: Observational studies have reported that elevated homocysteine (Hcy) levels are associated with the risk of cardiovascular disease (CVD). However, interventions that lower Hcy do not provide a corresponding risk reduction. Therefore, the causal role of Hcy in CVD remains unclear. This 5-year prospective study investigated the associations of Hcy levels, folate intake, and host factors with arterial stiffness among the general Japanese population. Methods: We prospectively recruited 658 participants (40 -69 years old) from the general population during regular health checkup examinations. Arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI) at baseline and the 5-year follow-up. Folate intake was estimated using a structured questionnaire. Genotyping was used to evaluate the MTHFR C677T and MS A2756G gene polymorphisms. Ultrafast liquid chromatography was used to measure total plasma Hcy levels. Association between these variables and CAVI values was evaluated using general linear regression and logistic regression models that were adjusted for atherosclerosis-related factors.

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“…[33][34][35] Several other genes in this pathway (eg, BHMT, MTHFR, MTR, MRTT, and CBS) regulate the metabolism of homocysteine, a risk factor of CHD. [36][37][38][39][40][41] Many genes in this gene set (GCLC, GCLM, MTHFR, MTHFD1, MTR, and MTRR) are also related to methylation processes, a potential, but understudied, mechanism for CVD. 42,43 Several genes in the Rac 1 cell-motility signaling pathway have also been recently implicated in CHD.…”

Section: Discussionmentioning

confidence: 99%

Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets

Fuentes¹,

Yang

Dávila‐Román³

et al. 2012

Eur J Hum Genet

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Genome-wide association (GWA) studies of complex diseases including coronary heart disease (CHD) challenge investigators attempting to identify relevant genetic variants among hundreds of thousands of markers being tested. A selection strategy based purely on statistical significance will result in many false negative findings after adjustment for multiple testing. Thus, an integrated analysis using information from the learned genetic pathways, molecular functions, and biological processes is desirable. In this study, we applied a customized method, variable set enrichment analysis (VSEA), to the Framingham Heart Study data (404 467 variants, n ¼ 6421) to evaluate enrichment of genetic association in 1395 gene sets for their contribution to CHD. We identified 25 gene sets with nominal Po0.01; at least four sets are previously known for their roles in CHD: vascular genesis (GO:0001570), fatty-acid biosynthetic process (GO:0006633), fatty-acid metabolic process (GO:0006631), and glycerolipid metabolic process (GO:0046486). Although the four gene sets include 170 genes, only three of the genes contain a variant ranked among the top 100 in single-variant association tests of the 404 467 variants tested. Significant enrichment for novel gene sets less known for their importance to CHD were also identified: Rac 1 cell-motility signaling pathway (h_rac1 Pathway, Po0.001) and sulfur amino-acid metabolic process (GO:0000096, Po0.001). In summary, we showed that the pathway-based VSEA can help prioritize association signals in GWA studies by identifying biologically plausible targets for downstream searches of genetic variants associated with CHD.

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The 2756A>G variant in the gene encoding methionine synthase: its relation with plasma homocysteine levels and risk of coronary heart disease in a Dutch case-control study

Cited by 61 publications

References 28 publications

The MTR A2756G polymorphism is associated with an increase of plasma homocysteine concentration in Brazilian individuals with Down syndrome

The MTR A2756G polymorphism is associated with an increase of plasma homocysteine concentration in Brazilian individuals with Down syndrome

Positive Association of Plasma Homocysteine Levels with Cardio-Ankle Vascular Index in a Prospective Study of Japanese Men from the General Population

Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets

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