An increased plasma total homocysteine level confers an independent risk of vascular disease similar to that of smoking or hyperlipidemia. It powerfully increases the risk associated with smoking and hypertension. It is time to undertake randomized controlled trials of the effect of vitamins that reduce plasma homocysteine levels on vascular disease risk.

Lower levels of folate and vitamin B6 confer an increased risk of atherosclerosis. Clinical trials are now required to evaluate the effect of treatment with these vitamins in the primary and secondary prevention of vascular diseases.

Background Plasma homocysteine levels are modulated by nutritional and genetic factors, among which is the enzyme methylenetetrahydrofolate reductase (MTHFR). A common defective (thermolabile) variant of this enzyme is causally associated with elevated plasma homocysteine, itself an independent risk factor for coronary heart disease.

Background Elevated plasma total homocysteine (tHcy) is a known risk factor for vascular disease. Gender, age, and circulating levels of folate, vitamins B 6 and B 12 affect tHcy levels.Objectives To study associations of gender and age with levels of plasma tHcy, and to examine the relationships of tHcy and circulating levels of folate, vitamins B 6 and B 12 with risk of vascular disease in men and women (pre-and post-menopausal). Material and methodsIn a multicentre case-control study in Europe, 750 patients (544 men, 206 women) with documented vascular disease of the coronary, cerebral, or peripheral vessels and 800 control subjects (570 men, 230 women) were enrolled. Plasma tHcy levels (fasting and after methionine loading) and circulating levels of the vitamins were measured. Adjustment for age and centre was carried out for all statistical analyses, with additional adjustment for serum creatinine and vitamins for the tHcy comparisons between the sexes and between cases and controls. Risk analyses included adjustment for creatinine and traditional risk factors. Relationships between age, gender and tHcy were studied among control subjects only.Results Fasting tHcy levels were lower in women than in men. Levels of tHcy showed a positive association with age, for both sexes. In the post-menopausal age category, female post-methionine load tHcy levels surpassed levels of men. Elevation of tHcy (defined as >80th percentile of controls) appeared to be at least as strong a risk factor for vascular disease in women as in men, even before the menopause. For post-methionine load tHcy, there was a 40% stronger association with vascular disease in women than in men. In both sexes, but especially in pre-menopausal women, low circulating levels of vitamin B 6 conferred a two-to threefold increased risk of vascular disease, independent of tHcy. In men, but not in women, low (defined as <20th percentile of controls) circulating folate levels were associated with a 50% increased risk of vascular disease. ConclusionsElevation of tHcy appears to be at least as strong a risk for vascular disease in women as men, even before the menopause. Our data indicate that associations of the various tHcy measurements (and the vitamins that determine them), with risks of vascular disease may differ between the sexes. The tHcy-independent relationship of vitamin B 6 with vascular disease indicates that it will be advisable to test the effects of vitamin B 6 in clinical trials. (Eur Heart J 1999; 20: 1234-1244)

There was a strong graded association between homocysteine and vascular risk in all genotypes. MTHFR genotype is a key determinant of plasma total homocysteine concentrations. The initially nonsignificant risk estimate associated with the TT genotype was strengthened after adjustment for conventional cardiovascular disease risk factors but was attenuated after adjustment for plasma folate and total homocysteine. The modest risk increase conferred by the TT genotype is mediated mainly by increased total homocysteine and low plasma folate concentrations.

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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