METHYLENETETRAHYDROFOLATE REDUCTASE GENE POLYMORPHISM AND ISCHEMIC STROKE IN JAPANESE

Hyperhomocyst(e)inemia has been identified as an independent risk fact or for atherosclerotic and thromboembolic diseases such as coronary ar tery disease, cerebral artery disease, and venous thrombosis. Recently , the alanine/valine (A/V) gene polymorphism of 5,10-methylenetetrahyd rofolate reductase (MTHFR), one of the key enzymes that catalyzes the remethylation of homocysteine, was reported. The VV genotype is correl ated with increased plasma homocyst(e)ine levels as a result of the re duced activity and increased thermolability of this enzyme. In this st udy, we examined the association between the V allele of the MTHFR gen e and ischemic stroke in an elderly Japanese population. The diagnosis of cerebral infarction of all study patients was confirmed by CT of t he brain. The MTHFR genotype was analyzed by polymerase chain reaction followed by HinfI digestion. In 256 stroke patients and 325 control s ubjects, the frequencies of the V allele were 0.45 and 0.32, respectiv ely. The odds ratios and 95% confidence intervals adjusted for the oth er risk factors were, respectively, 1.51 (1.02 to 2.23) for the AV gen otype and 3.35 (1.94 to 5.77) for the VV genotype compared with the AA genotype. Both of these effects were statistically significant (P=0.0 41 and P<0.001, respectively). In patients with multiple infarcts in p articular, the allele frequency of the V mutation was 0.56, and the as sociation between the V allele and stroke was highly significant. Plas ma homocyst(e)ine levels were significantly higher in patients with th e VV genotype than in patients with the AA or AV genotype, especially those with low plasma folate levels. The V allele of the MTHFR gene wa s significantly associated with cerebral infarction in an elderly Japa nese population in a codominant manner. The VV genotype may contribute to risk for ischemic stroke through a predisposition to increased pla sma homocyst(e)ine levels, and dietary folate supplementation may be o f benefit, particularly to patients with this genotype.