The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations

Epidemiological evidence has revealed that an elevated plasma homocysteine level (hyperhomocysteinemia) confers an increased risk of cardiovascular di sease and neural tube defects. Hyperhomocysteinemia is caused by both nutri tional (e.g. folate, vitamins B-6 and B-12) and genetic factors, including functional polymorphisms of key enzymes involved in homocysteine metabolism . One such enzyme, methionine synthase reductase (MTRR), maintains adequate levels of methylcob(III)alamin, the activated cofactor for methionine synt hase, which catalyzes the remethylation of homocysteine to methionine. A co mmon MTRR polymorphism, i.e. a 66 A --> G substitution specifying an isoleu cine to methionine substitution (I22M), was recently identified. To assess the influence of this polymorphism on total plasma homocysteine (tHcy), we undertook a genotype/phenotype analysis in a study population of 601 Northe rn-Irish men, aged 30-49, for which biochemical and genetic data relevant t o folate/homocysteine metabolism had already been acquired. The 66AA genoty pe has a frequency of 29% in this population. We established that there was a significant influence of MTRR genotype on tHcy ranking (P = 0.004) and t hat the 66AA genotype contributes to a moderate increase in tHcy levels acr oss the distribution [OR 1.59 (95% CI: 1.10-2.25) for the 66AA genotype to be in the upper half of the tHcy distribution, P = 0.03]. The homocysteine- elevating effect of the 66AA genotype is independent of serum folate, vitam in B-12 and vitamin B-6 levels. Based on published estimates of the enhance d cardiovascular disease risk conferred by defined increments of plasma tHc y, we estimate that 66AA homozygotes have, on average, an approximately 4% increase in cardiovascular disease risk compared to 66GG homozygotes. This study provides the first evidence that the MTRR A66G polymorphism significa ntly influences the circulating tHcy concentration. (C) 2001 Elsevier Scien ce Ireland Ltd. All rights reserved.