A common polymorphism in methionine synthase reductase increases risk of premature coronary artery disease

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 tetrahydrofo late, as well as for maintaining homocysteine concentrations at nontoxic le vels. 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 alter ations in levels of homocysteine, folate, and vitamin B-12 and with risk of developing premature coronary artery disease (CAD), in a population of ind ividuals presenting for cardiac catheterization procedures. and with risk o f developing premature coronary Methods We screened 180 individuals aged < 58 years with angiographically d ocumented coronary-artery occlusions or occlusion-free major arteries for t he presence of the 66A -> G MTRR polymorphism using a polymerase-chain-reac tion-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 gro ups. There was no difference in fasting levels of plasma total homocysteine , serum folate, and vitamin B-12 among the three MTRR genotypes. Conclusions Our findings suggest that the GG genotype of MTRR is a signific ant risk factor for the development of premature CAD, by a mechanism indepe ndent of the detrimental vascular effects of hyperhomocysteinemia. This ass ociation needs to be confirmed in other studies.