A Common Polymorphism in Methionine Synthase Reductase Increases Risk of Premature Coronary Artery Disease

Abstract

Background

Methionine synthase reductase (MTRR) catalyzes the regeneration of methylcobalamin, a cofactor of methionine synthase, an enzyme essential for maintaining adequate intracellular pools of methionine and tetrahydrofolate, as well as for maintaining homocysteine concentrations at nontoxic levels. We recently identified a common A → G polymorphism at position 66 of the cDNA sequence of MTRR; this variant was associated with a greater than normal risk for spina bifida in the presence of low levels of cobalamin.

Objective

To investigate whether the polymorphism was associated with alterations in levels of homocysteine, folate, and vitamin B₁₂, and with risk of developing premature coronary artery disease (CAD), in a population of individuals presenting for cardiac catheterization procedures.

Methods

We screened 180 individuals aged < 58 years with angiographically documented coronary-artery occlusions or occlusion-free major arteries for the presence of the 66A → G MTRR polymorphism using a polymerase-chain-reaction-based assay.

Results

We identified a trend in risk of premature CAD across the genotype groups (P =0.03) with a sex-adjusted relative risk of premature CAD equal to 1.49 (95% confidence interval 1.10–2.03) for the GG versus AA genotype groups. There was no difference in fasting levels of plasma total homocysteine, serum folate, and vitamin B₁₂ among the three MTRR genotypes.

Conclusions

Our findings suggest that the GG genotype of MTRR is a significant risk factor for the development of premature CAD, by a mechanism independent of the detrimental vascular effects of hyperhomocysteinemia. This association needs to be confirmed in other studies.