High Homocysteine and Stroke: Cause or Effect?

Abstracts & Commentary

Synopsis: The observed increase in risk of stroke among individuals homozygous for the MTHFR T allele is close to that predicted from the differences in homocysteine concentration conferred by this variant.

Sources: Casas JP, et al. Homocysteine and Stroke: Evidence on a Causal Link From Mendelian Randomization. Lancet. 2005;365:224-232; Hankey GJ, et al. Homocysteine and Stroke. Lancet. 2005;365:194-195.

Data from cohort and case-controlled studies have shown a positive, dose-related association between serum total homocysteine (tHcy) concentration and the risk of stroke.1 Homocysteine concentration is related to smoking, blood pressure, existing atherosclerosis, and renal impairment. In addition, a stronger association between tHcy and stroke has been reported in retrospective studies in which researchers collected blood after stroke rather that in prospective studies, suggesting that acute stroke may increase tHcy. Therefore, whether raised tHcy causes stoke has not been established, and no randomized trial has shown that lowering tHcy reduces stroke risk.2

Casas and colleagues used Mendelian randomization to study the association between tHcy and stroke. They noted that individuals homozygous for a specific CT polymorphism of the methylene tetrahydrofolate reductace (MTHFR) gene have 20% higher tHcy concentrations (about 2 mol/L) than those with the CC genotype.3 Therefore, they reasoned that if a higher tHcy concentration is pathogenetic, TT homozygotes (about 10% of the population) should be at increased risk of stroke.

Casas et al did a meta-analysis of 111 studies up to the end of 2003 that examined either the association between tHcy and MTHFR polymorphism and the risk of stroke (n = 13,928). They found that individuals homogeneous (TT) for the MTHFR polymorphism have a significantly higher tHcy (mean difference 1.93 mol/L) and a greater risk of stroke (odds ratio 1:26) than individuals who are homozygous (CC).

The observed increase in stroke risk among individuals homogeneous for the MTHFR T allele is close to that predicted from differences in tHcy concentration conferred by this polymorphism and, therefore, is consistent with a causal relation between tHcy concentration and stroke.


It is important to determine whether tHcy causes stroke because serum levels of tHcy can be lowered by the administration of folic acid and vitamins B6 and B12.4 The association between tHcy and stroke described by Casas et al implies that lowering tHcy by 3 mol/L with vitamins should reduce the overall risk of stroke by about 20%. Nevertheless, the Vitamins in Stroke Prevention (VISP) trial reported that lowering tHcy by 2 mol/L with multivitamin therapy failed to prevent recurrent stroke.2 As pointed out by Hankey and colleagues, VISP was statistically under-powered and could not exclude the possibility that vitamin therapy reduced relative stroke risk by up to 20%.

In addition, as pointed out by Casas et al, the effect of tHcy was small compared with those of the classic cardiovascular risk factors and, therefore, their results do not support routine screening of MTHFR genotype and tHcy concentration as a cost-effective means to detect individuals at risk for stroke. Furthermore, as Hankey et al stated in their editorial, even if tHcy is established as a cause of stroke, it may not be safe to prescribe long-term, high dose vitamins because of potential drug interactions and unknown biological effects.

Therefore, at the present time, clinicians can choose to administer vitamins to lower tHcy and/or recommend changes in lifestyle, pending the validation of vitamin therapy to prevent stroke and cardiovascular events by adequately powered randomized controlled trials. — John Caronna

Dr. Caronna, Vice-Chairman, Department of Neurology, Cornell University Medical Center; Professor of Clinical Neurology, New York Hospital, is Associate Editor of Neurology Alert.


1. The Homocysteine Studies Collaboration. JAMA. 2002; 288:2015-2022.

2. Toole JF, et al. JAMA. 2004;291:565-575.

3. Klak M, et al. JAMA. 2002;288:2023-2031.

4. He K, et al. Stroke. 2004;35:169-174.