Methylenetetrahydrofolate Reductase Polymorphism, Plasma Folate, Homocysteine, and Risk of Myocardial Infarction in US Physicians

Abstract

Background- Hyperhomocysteinemia appears to be an independent risk factor for coronary disease. Elevated levels of plasma total homocysteine (tHCY) can result from genetic or nutrient-related disturbances in the transsulfuration or remethylation pathways for homocysteine metabolism. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate, which serves as a methyl donor for remethylation of homocysteine to methionine. A common mutation in MTHFR recently has been identified. Methods and Results- We assessed the polymorphism in MTHFR, plasma tHCY, and folate using baseline blood levels among 293 Physicians' Health Study participants who developed myocardial infarction (MI) during up to 8 years of follow-up and 290 control subjects. The frequency of the three genotypes was (-/-) (homozygous normal), 47%; (+/-) (heterozygous), 41%; and (+/+) (homozygous mutant), 12%, with a similar distribution among both MI case patients and control subjects. Compared with those with genotype (-/-), the relative risk (RR) of MI among those with (-/-) was 1.1 (95% CI, 0.8 to 1.5), and it was 0.8 (0.5 to 1.4) for the (+/+) genotype; none of these RRs were statistically significant. However, those with genotype (+/+) had an increased mean tHCY level (mean+/-SEM, 12.6+/-0.5 nmol/mL), compared with those with genotype (-/-) (10.6+/-0.3) (P<.01). This difference was most marked among men with low folate levels (the lowest quartile distribution of the control subjects): those with genotype (+/+) had tHCY levels of 16.0+/-1.1 nmol/mL, compared with 12.3+/-0.6 nmol/mL (P<.001) for genotype (-/-). Conclusions- In this population, MTHFR polymorphism was associated with higher homocysteine levels but not with risk of MI. A gene-environment interaction might increase the risk by elevating tHCY, especially when folate intake is low.