Genetic and nongenetic factors influencing plasma homocysteine levels in patients with ischemic cerebrovascular disease and in healthy control subjects

Moderately elevated plasma homocysteine levels have been established as an independent risk factor for atherosclerosis and its complications, includin g cerebrovascular disease. A common mutation (C677T) in the gene encoding f or the enzyme methylenetetrahydrofolate reductase (MTHFR) has been linked t o increased plasma homocysteine levels in homozygous carriers, particularly in the presence of low folate levels. However, the results of most of the previous studies suggest that the C677T MTHFR mutation is not a significant risk factor for arterial disease. This discrepancy might, at least partly, be due to the fact that plasma homocysteine levels are influenced by sever al other factors, including age, gender, renal function, and vitamin status . We investigated the relation between plasma homocysteine levels, the C677 T MTHFR mutation, and these other factors in a population of 96 patients wi th transient ischemic attacks or minor strokes and in 96 age- and sex-match ed healthy control subjects. We further tested the value of a multivariate model for the prediction of plasma homocysteine levels under particular con sideration of the MTHFR mutation status. In the patients, plasma homocystei ne levels were significantly higher than in the healthy control subjects. W ith regard to the MTHFR mutation, the distribution of the C/C, C/T,and T/T genotypes was not significantly different between patients and healthy cont rol subjects. Univariate (linear regression) analysis revealed significant (positive) correlations between plasma homocysteine levels on the one hand and age and creatinine on the other, the latter particularly in subjects wi th creatinine levels in the upper quartile. Significant (negative) correlat ions were found between plasma homocysteine levels, vitamin B-12, and folat e levels. However, these relations could much better be expressed by means of a multiplicative regression model. T/T subjects exhibited slightly highe r homocysteine levels than C/C and C/T subjects; however, the differences b etween the 3 genotypes were not significant. Multivariate (stepwise regress ion) analysis revealed age, vitamin B-12 levels, folate levels, and creatin ine levels as significant independent variables influencing plasma homocyst eine levels, whereas the MTHFR mutation status and gender were removed from the model. Considering all 192 subjects, only 28.8% of the variance of pla sma homocysteine levels could be accounted for by the model. However, in ho mozygous carriers of the MTHFR mutation, the predictive power of the model is very high, explaining 76.1% of the variance of plasma homocysteine level s. According to our results, the C677T mutation does not constitute a major risk factor for transient ischemic attack or minor stroke, even under cons ideration of other possibly confounding factors that are known to affect pl asma homocysteine levels. However, it is possible to predict plasma homocys teine levels in homozygous carriers of the mutation with high accuracy. The knowledge of the MTHFR mutation status may therefore help to identify subj ects at high risk for hyperhomocysteinemia.