Investigations of a common genetic variant in betaine–homocysteine methyltransferase (BHMT) in coronary artery disease

Weisberg, Ilan; Park, Eric; Ballman, Karla V.; Berger, Peter B.; Nunn, Martha E.; Suh, Daniel; Breksa, Andrew P.; Garrow, Timothy A.; Rozen, Rima

doi:10.1016/s0021-9150(03)00010-8

Cited by 77 publications

(58 citation statements)

References 29 publications

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“…Both BHMT and MTRR are involved in maintaining cellular levels of methionine; BHMT catalyzes the re-methylation of homocysteine to methionine, predominantly in the liver and kidney (49), whereas MTRR activates MTR, which also catalyzes the re-methylation of homocysteine to methionine in various tissues. (50,51) and spina bifida (52) associated with Gln/Gln versus Arg/Arg at BHMT codon 239 have been suggested among three previous studies. However, another study observed no association with spina bifida (53), and Arg 239 Gln has not been associated with altered BHMT activity (51) or homocysteine levels (50).…”

Section: Resultsmentioning

confidence: 86%

Nonsynonymous Polymorphisms in Genes in the One-Carbon Metabolism Pathway and Associations with Colorectal Cancer

Koushik

Kraft

Fuchs

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The Ala 222 Val single nucleotide polymorphism (SNP) in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in one-carbon metabolism, has been associated with colorectal cancer risk. Many enzymes are involved in one-carbon metabolism, and SNPs in the corresponding genes may play a role in colorectal carcinogenesis. We examined 24 nonsynonymous SNPs in 13 genes involved in the one-carbon metabolism pathway in relation to the risk of colorectal cancer in a case-control study nested in the

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Section: Resultsmentioning

confidence: 86%

Nonsynonymous Polymorphisms in Genes in the One-Carbon Metabolism Pathway and Associations with Colorectal Cancer

Koushik

Kraft

Fuchs

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…The decreased Km of the alloenzyme may be responsible for the increased efficiency of Hcy remethylation, which requires betaine as a methyl group donor, [32], reducing Hcy concentration. Furthermore, studies have suggested a protective role of the homozygous AA genotype against neural tube defects [33] and cardiovascular disease [34], suggesting that the BHMT 742 G allele may have a deleterious effect on Hcy metabolism. Supporting this hypothesis and consistent with our findings, the BHMT 742 AA genotype was associated with lower Hcy concentrations in a previous study [33].…”

Section: Discussionmentioning

confidence: 99%

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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“…In a normally functioning metabolic state, methionine produces homocysteine as an intermediate step before either transsulfuration via cystathionine into cysteine or remethylation to methionine [20]. This remethylation may be folate-dependent, or may use betaine, a metabolite of choline [21]. Methionine synthase, a vitamin B 12 -dependent enzyme, utilizes 5-methyltetrahydrofolate as the carbon donor for folate-dependent homocysteine remethylation; methionine synthase requires activation by methionine synthase reductase (MTRR).…”

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confidence: 99%

“…Betainehomocysteine methyltransferase (BHMT) utilizes betaine as the carbon donor. Therefore, the improper function of remethylation enzymes, due to mutation or to insufficient intake of relevant nutrients, may result in elevated homocysteine levels and contribute to thrombophilias, and possibly, placental abruption.This study focuses on variants in two of the enzymes responsible for the remethylation of homocysteine, MTRR 66A→G and BHMT 742G→A [21]. While BHMT, unlike MTRR, is not directly involved in the folate-dependent pathway, experiments have shown that homocysteine flux through the BHMT pathway is enhanced when folate-dependent remethylation is disrupted [22].…”

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confidence: 99%

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Polymorphisms in methionine synthase reductase and betaine-homocysteine S-methyltransferase genes: Risk of placental abruption

Ananth

Elsasser

Kinzler

et al. 2007

Molecular Genetics and Metabolism

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Objective-Methionine Synthase Reductase (MTRR) and Betaine-Homocysteine SMethyltransferase (BHMT) are 2 enzymes that regulate homocysteine metabolism. Elevated homocysteine (hyperhomocysteinemia) is associated with adverse pregnancy outcomes and vascular disease. We assessed whether polymorphisms in MTRR (66A→G; I22M) and BHMT (742G→A; R239Q) were associated with abruption. We further evaluated whether homocysteine levels differed between cases and controls for MTRR and BHMT genotypes.Methods-Data were derived from the New Jersey Placental Abruption Study (NJ-PAS)-an ongoing, multicenter, case-control study since August 2002. Women with a clinical diagnosis of abruption were recruited as incident cases (n=196), and controls (n=191) were matched to cases based on maternal race/ethnicity and parity. Total plasma homocysteine concentrations were evaluated in a subset of 136 cases and 136 controls. DNA was genotyped for the MTRR and BHMT polymorphisms.Results-Frequencies of the minor allele of MTRR were 40.8% and 42.2% in cases and controls, respectively (adjusted OR 0.79, 95% CI 0.45, 1.40). The corresponding rates for BHMT were 33. 9% and 31.7%, respectively (adjusted OR 1.93, 95% CI 0.99, 4.09). Distributions for the homozygous mutant form of MTRR were similar between cases and controls (OR 1.18, 95% CI 0.62, 2.24). The rate of homozygous mutant BHMT genotype was 2.8-fold (OR 2.82, 95% CI 1.84, 4.97) higher in cases than controls. Stratification of analyses based on maternal race did not reveal any patterns in association.Conclusions-In this population, there was an association between the homozygous mutant form of BHMT (742G→A) polymorphism and increased risk for placental abruption.Correspondence and reprint requests Cande V. Ananth, PhD, MPH, Division of Epidemiology and Biostatistics, Department of Obstetrics, Gynecology, and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, 125 Paterson Street, New Brunswick, NJ 08901-1977, Tel: (732) 235-6627, Email: cande.ananth@umdnj.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ;5;7;8;9;10;11;12; 13;14;15;16]. Women with a previous abruption are at greatest risk (over 10-fold) risk of recurrent abruption, suggesting a strong genetic etiologic mechanism [17;18]. NIH Public AccessStudies have shown that folate deficiency is associated with increased homocysteine levels [19]. In a normally functioning metabolic state, methionine produces homocysteine as an intermediate step before either transsulfuration via cystathionine into cysteine or remethylation to methionine [20]. This remethylation may be ...

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Investigations of a common genetic variant in betaine–homocysteine methyltransferase (BHMT) in coronary artery disease

Cited by 77 publications

References 29 publications

Nonsynonymous Polymorphisms in Genes in the One-Carbon Metabolism Pathway and Associations with Colorectal Cancer

Nonsynonymous Polymorphisms in Genes in the One-Carbon Metabolism Pathway and Associations with Colorectal Cancer

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

Polymorphisms in methionine synthase reductase and betaine-homocysteine S-methyltransferase genes: Risk of placental abruption

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