Polymorphisms in the CBS Gene Associated with Decreased Risk of Coronary Artery Disease and Increased Responsiveness to Total Homocysteine Lowering by Folic Acid

Kruger, Warren D.; Evans, Alison A.; Wang, Liqun; Malinow, M. R.; Duell, P. Barton; Anderson, Peter H.; Block, Peter C.; Hess, David L.; Graf, Eric E.; Upson, B.

doi:10.1006/mgme.2000.2993

Cited by 52 publications

(27 citation statements)

References 18 publications

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“…Several other polymorphisms, including CBS 1080CϾT and 699CϾT (22,23 ), transcobalamin-II (TCII) 776CϾG (24 -28 ) and 67AϾG (29 ), reduced folate carrier-1 (RFC1) 80GϾA (30 -33 ), betaine homocysteine methyltransferase (BHMT) 742GϾA (34,35 ), and paraoxonase-1 (PON1) 575AϾG and 163TϾA (36,37 ), have been related to folate or Hcy status, and their possible associations with risk of cardiovascular disease and other diseases are under investigation.…”

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High-Level Multiplex Genotyping of Polymorphisms Involved in Folate or Homocysteine Metabolism by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry

2004

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Background: Increased plasma total homocysteine (tHcy), a risk factor for cardiovascular disease, is related to genetic, environmental, and nutritional factors, in particular folate status. Future large epidemiologic studies of the genetic basis of hyperhomocysteinemia will require high-throughput assays for polymorphisms of genes related to folate and Hcy metabolism. Method: We developed a high-level multiplex genotyping method based on matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry (MALDI-TOF MS) for the detection of 12 polymorphisms in 8 genes involved in folate or Hcy metabolism. The assay includes methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G, cystathionine ␤-synthase (CBS) 844ins68 and 699C>T, transcobalamin II (TCII) 776C>G and 67A>G, reduced folate carrier-1 (RFC1) 80G>A, paraoxonase-1 (PON1) 575A>G and 163T>A, and betaine homocysteine methyltransferase (BHMT) 742G>A. Results: The failure rate of the assay was <1.7% and was attributable to unsuccessful DNA purification, nanoliter dispensing, and spectrum calibration. Most errors were related to identification of heterozygotes as homozygotes. The mean error rate was 0.26%, and error rates differed for the various single-nucleotide polymorphisms. Identification of CBS 844ins68 was carried out by a semiquantitative approach. The throughput of the

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High-Level Multiplex Genotyping of Polymorphisms Involved in Folate or Homocysteine Metabolism by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry

2004

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“…In a study of 304 individuals, it was found that 20% actually had elevations in plasma homocysteine levels after 3 weeks of folic acid supplementation, 14 which correlated with the status of singlenucleotide polymorphisms in the cystathionine ␤-synthase (Cbs) gene. 15 It has also been observed that end-stage renal disease patients as a group have extremely elevated plasma homocysteine despite vitamin therapy. 16 Thus, there is a need for additional strategies to lower plasma homocysteine.…”

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Modulation of Cystathionine β-Synthase Level Regulates Total Serum Homocysteine in Mice

Wang

Jhee

Xiang

et al. 2004

Circulation Research

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147

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Abstract-Elevated total plasma homocysteine is an independent risk factor in the development of vascular disease in humans. Cystathionine ␤-synthase (CBS) is an enzyme that condenses homocysteine with serine to form cystathionine. In this article, we describe the effects of modulating CBS activity using a transgenic mouse that contains the human CBS cDNA under control of the zinc-inducible metallothionein promoter (Tg-CBS). In the presence of zinc, Tg-CBS mice have a 2-to 4-fold increase in liver and kidney CBS activity compared with nontransgenic littermates. Transgenic mice on standard mouse chow had a 45% decrease in their serum homocysteine (12.1 to 7.2 mol/L; PϽ0.0001) when zinc was added to drinking water, although zinc had minimal effect on their nontransgenic siblings (13.2 mol/L versus 13.0 mol/L; PϭNS). Tg-CBS mice maintained on a high-methionine, low-folate diet also had significantly lower serum homocysteine compared with control animals (179 mol/L versus 242 mol/L; PϽ0.02). CBS overexpression also significantly lowered serum cysteinylglycine (3.6 versus 2.8 mol/L; PϽ0.003) levels and reduced the levels of many amino acids in the liver. We also found that expression of Tg-CBS rescued the severe hyperhomocysteinemia and neonatal lethality of Cbs deletion animals. Our results show that elevating CBS activity is an effective method to lower plasma homocysteine levels. In addition, the creation of an inducible mouse system to modulate plasma homocysteine will also be useful in the study of homocysteine-related vascular disease.

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“…O folato é um fator de risco relacionado com a homocisteína (23,24), e a administração de ácido fóli-co combinada com as vitaminas B12 e B6 reduz a homocisteína nos pacientes com DAC (25). Além disso, os pacientes 677T homozigotos apresentam concentrações plasmáticas de homocisteína elevadas, principalmente quando o folato está baixo (26), e estes podem ser mais responsivos à suplementação de folato (27). Contudo, no presente estudo não foi observada uma correlação inversa, estatisticamente significante para as concentrações de folato e homocisteína, fato este que pode ser justificado pela limitação do estudo no que se refere ao tamanho da amostra, quando aplicados os testes estatísticos.…”

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Avaliação da relação entre o polimorfismo C677T no gene para MTHFR e a concentração plasmática de homocisteína na doença arterial coronariana

Muniz

Siqueira

Fonseca

et al. 2006

Arq Bras Endocrinol Metab

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RESUMOObjetivo: O objetivo deste trabalho é determinar a prevalência do polimorfismo C677T do gene metilenotetraidrofolato redutase (MTHFR) e associá-la com a concentração plasmática de homocisteína plasmáti-ca na doença arterial coronariana (DAC). Métodos: Foram avaliados 93 pacientes com DAC documentada, atendidos no Hospital Universitário Oswaldo Cruz (Recife, PE, Brasil), e 108 controles sem a doença. Foram determinados os perfis lipídicos de pacientes e controles. As concentrações plasmáticas de homocisteína e folato foram determinadas por HPLC e quimioluminescência, respectivamente. A genotipagem foi realizada por RFLP/PCR. Resultados: Os grupos de pacientes e controles foram homogêneos quanto aos perfis genéticos do polimorfismo investigado. Nos pacientes, as concentrações plasmáticas médias de homocisteina (11,7 ± 4,4 µmol/L) e de folato (6,22 ± 3,0 ng/dL) foram estatisticamente diferentes daquelas observadas nos controles (8,84 ± 3,2 µmol/L e 7,69 ± 3,1 ng/dL, respectivamente), ao nível de significância de 0,05. Entretanto, não houve correlação entre concentração plasmática de homocisteína e folato nos pacientes (r= -0,202). Não foi observada associação entre a homozigosidade 677TT para MTHFR e a concentração plasmática de homocisteína sérica (p= 0,634). A comparação dos casos e controles que apresentaram simultaneamente alta concentração plasmática de homocisteína e baixa concentração de folato, resultou numa razão de chance superior à de cada variável analisada independentemente (RC= 11,9; IC 95%= 4,16-34,42, p< 0,01). Conclusões: A mutação C677T não parece ser um fator genético importante capaz de explicar a hiperhomocisteinemia moderada observada nos pacientes com DAC. Outros fatores, ambientais e genéticos, devem ser investigados. Objective: The aim of this study is to determine the prevalence of C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism and correlate it with plasma homocysteine levels in coronary artery disease (CAD). Methods: Ninety-three patients with documented CAD from Hospital Universitário Oswaldo Cruz (Recife, PE, Brazil) and 108 healthy controls were evaluated. Homocysteine and folate levels were determined by HPLC and chemoluminescence, respectively, and lipid profile was considered. Genotyping was done by RFLP/PCR. Results: The groups were homogeneous for the C677T polymorphisms. The homocysteine level in cases (11.7 µmol/L) was statistically different from that observed in controls (8.84 µmol/L, p< 0.05). It was also observed that 72% of the patients had homocysteine values above12 µmol/L while the control group presented only 32% in this range. There was no relationship between homozigosity for the

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Polymorphisms in the CBS Gene Associated with Decreased Risk of Coronary Artery Disease and Increased Responsiveness to Total Homocysteine Lowering by Folic Acid

Cited by 52 publications

References 18 publications

High-Level Multiplex Genotyping of Polymorphisms Involved in Folate or Homocysteine Metabolism by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry

High-Level Multiplex Genotyping of Polymorphisms Involved in Folate or Homocysteine Metabolism by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry

Modulation of Cystathionine β-Synthase Level Regulates Total Serum Homocysteine in Mice

Avaliação da relação entre o polimorfismo C677T no gene para MTHFR e a concentração plasmática de homocisteína na doença arterial coronariana

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