This may be caused by genetic defects in the enzymes involved in homocysteine metabolism such as deficiencies of cystathionine -synthase and methylenetetrahydrofolate reductase (MTHFR), involved in the transsulfuration and remethylation pathways, respec- tively, or by a thermolabile variant of MTHFR that results from a point mutation in which cytosine is replaced by thymidine at position 677 (MTHFR C677T).759 Hyperhomocysteinemia also is caused by nutritional deficiencies of pyridoxine (vita- ), a cofactor of cystathionine -synthase, and of folic acid and cobalamin (vitamin B12 ), cofactors of MTHFR.760 Decreased renal clearance of homocysteine in patients with chronic renal failure may contribute to hyperhomocysteinemia. Elevated levels of plasma homocysteine are associated with 2- to 3-fold increased risk for atherosclerotic vascu- lar disease, including stroke.761 767 Carotid IMT and carotid artery stenosis are increased in people with elevated homo- In the Study of Health Assessment and Risk in Ethnic Groups (SHARE), a cross-sectional study of South Asian Chinese and white Canadians, plasma homocys- teine >11.7 mol/L, but not MTHFR C677T, was associated with increased carotid IMT.771 Several recent investigations found that the relationship between homocysteine levels and carotid IMT was eliminated after adjustment for other cardiovascular risk factors or renal function.772,773 One meta- analysis of epidemiological studies found a 19% (95% CI, 5 31) reduction in odds of stroke per 25% lower homo- cysteine concentration after adjustment for smoking, SBP, Another meta-analysis found that for each 5- mol/L increase in homocysteine, the odds of stroke increased by 59% (95% CI, 29 96), and for each 3- mol/L decrease in homocysteine, the odds of stroke decreased by A further line of evidence support- ing a causal role for homocysteine in a stroke is a meta-anal- ysis of 29 studies comparing the MTHFR C677T genotype between 4454 stroke patients and 7586 control subjects. 