Plasma Homocysteine as a Risk Factor for Vascular Disease

Graham, Ian; Daly, Leslie; Refsum, Helga; Robinson, Killian; M, Lars E. Brattstr; Ueland, Per Magne; Palma-Reis, Roberto; Boers, G.H.J.; Sheahan, Richard G.; Israelsson, Bodil; Uiterwaal, Cuno S.P.M.; Meleady, Raymond; McMaster, Dorothy; Verhoff, Petra; Witteman, Jacqueline C. M.; Rubba, P.; Bellet, H.; Wautrecht, Jan; Valk, Harold W. de; Luis, Armando C. Sales; Parrot-Roulaud, F.; Tan, Kaixuan; Higgins, Isabella; Garçon, Danielle; Medrano, Maria Jos; Candito, M.; Evans, Alun; Andria, Generoso

doi:10.1097/00132586-199808000-00060

Cited by 24 publications

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“…10 This is a homocysteine level known to confer a 2-to 3-fold risk of vascular disease. 1,5 However, the association between elevated plasma homocysteine and the thermolabile genotype is dependent on serum folate status. 10,11 Significant gene-nutritional interactions are therefore likely, and twin studies indicate that approximately half of homocysteine variation may be a result of genetic factors.…”

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confidence: 99%

Genetic Analysis of the Thermolabile Variant of 5,10-Methylenetetrahydrofolate Reductase as a Risk Factor for Ischemic Stroke

Harmon

Doyle

Meleady

et al. 1999

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Abstract-Mild hyperhomocysteinemia is a risk factor for atherosclerotic vascular disease. Homozygosity for the C677T mutation in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR) is frequently associated with hyperhomocysteinemia, particularly in individuals with low levels of serum folate, and has been directly associated with cardiovascular disease in certain populations. The purpose of this study was to establish whether the C677T mutation, which causes thermolabile MTHFR, is a risk factor for ischemic stroke in the Irish population. The homozygous C677T genotype has previously been associated with coronary heart disease in Ireland. We collected blood from 174 individuals (minimum age 60 years) who had suffered an ischemic stroke that was confirmed by computed tomography brain scan. Control subjects (nϭ183) aged Ն60 years, who had never suffered a stroke or transient ischemic attack, were recruited from hospitals and active retirement groups in the same geographical area. MTHFR genotypes were determined and other known risk factors for stroke were documented. In the control group, the frequency of subjects with the homozygous C677T genotype was 10.4%. In patients who had suffered ischemic stroke, the frequency was 15.5%. This difference was not statistically significant. 2 In addition it is associated with thickening of the carotid arterial wall. 3,4 The magnitude of the risk of vascular disease conferred by hyperhomocysteinemia varies between populations. A meta-analysis of the data indicates that hyperhomocysteinemia confers at least a 2.5-fold increased risk of stroke. 5 Homocysteine is a sulphur amino acid generated by the many transmethylation reactions that consume S-adenosyl methionine (SAM) (Figure). Homocysteine is remethylated to methionine (from which SAM is then regenerated) by the vitamin B12-dependent enzyme methionine synthase. This remethylation uses 5-methyl tetrahydrofolate as the methyl donor. 5-methyl tetrahydrofolate is itself generated from 5,10-methylene tetrahydrofolate by the enzyme 5, 10-methylenetetrahydrofolate reductase (MTHFR). Under normal circumstances, homocysteine can be irreversibly degraded by the transsulfuration pathway, the first step of which is catalyzed by the vitamin B6-dependent enzyme cystathionine ␤-synthase (CBS).Plasma homocysteine levels are therefore influenced by both nutritional (folate and vitamins B12 and B6) and genetic factors, including mutations in the genes encoding methionine synthase, CBS, and MTHFR. In particular, a biochemically defined "thermolabile" variant of MTHFR is associated with moderate hyperhomocysteinemia. 6 The genetic change underlying thermolabile MTHFR is a C to T base transition at nucleotide 677 in the MTHFR cDNA, 7,8 which results in the substitution of valine for alanine. 8 The frequency of homozygotes for the thermolabile MTHFR mutation is between 5% and 15% in different European populations. 9 Recently, homozygosity for the thermolabile genotype has been associated with a nearly 10-fold increased risk of an indivi...

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Genetic Analysis of the Thermolabile Variant of 5,10-Methylenetetrahydrofolate Reductase as a Risk Factor for Ischemic Stroke

Harmon

Doyle

Meleady

et al. 1999

ATVB

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“…Furthermore, the relationship between plasma total homocysteine and cardiovascular disease seems to be graded with no apparent threshold (Refsum et al, 1998). Moreover, an elevated plasma total homocysteine concentration is besides a strong independent risk factor an even stronger risk factor in combination with the established risk factors smoking and hypertension (Graham et al, 1997). Intervention studies have shown that supplementation with folic acid lowers plasma total homocysteine concentrations (Chapter 2 and 4 of this thesis, (Homocysteine Lowering Trialists' Collaboration, 1998;Ward et al, 1997).…”

Section: Folic Acid/folate For the Prevention Of Cardiovascular Diseasementioning

confidence: 99%

“…Furthermore, dietary folate and folic acid both effectively decrease total homocysteine levels in plasma (Brouwer et al, 1999;Homocysteine Lowering Trialists' Collaboration, 1998, Chapter 6). This is important because an elevated plasma homocysteine concentration has been identified as an independent risk factor for cardiovascular disease (Boushey et al, 1995;Graham et al, 1997) Plasma homocysteine concentration can be regarded as a functional indicator of the folate status (Jacob et al, 1995) This review will discuss the factors influencing bioavailability of natural food folate and of folic acid from fortified food products It also includes discussion of the efficacy of folate and folic acid in decreasing plasma homocysteine levels.…”

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confidence: 99%