The balance of evidence from observational studies suggests that elevated homocysteine levels are associated with increased risk of carotid artery disease and stroke. There is however a paucity of prospective studies. There are also concerns regarding confounding due to factors associated with hyperhomocysteinemia, including renal impairment, an atherogenic diet and cigarette smoking. Homozygosity for a defective thermolabile variant of MTHFR, a common genetic polymorphism which results in hyperhomocysteinemia, has not been consistently linked with stroke or other vascular disease. There is a need for additional prospective studies with data on relevant confounders, sufficient power to characterise the form of the association between homocysteine concentrations and stroke risk, whether linear or threshold, and power to study interactions between homocysteine, other dietary markers and established stroke risk factors such as smoking and hypertension. Similarly, the evidence linking hyperhomocysteinemia with hypertension is limited and inconsistent. Given the biological mechanisms proposed in support of the homocysteine-CVD hypothesis, one would predict a positive association between homocysteine and blood pressure. There is a need to address this hypothesis directly in studies with reliable measurements of both homocysteine and blood pressure. Ultimately, the case for a causal role for elevated homocysteine levels in vascular disease, including hypertension and stroke, will depend on data from randomised controlled trials of homocysteine lowering interventions. Given the high prevalence of hyperhomocysteinemia in apparently well nourished populations and the tendency for homocysteine concentrations to increase with age, modest effects of homocysteine on stroke risk will have profound implications for public health.
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