Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations

Elevation in plasma homocysteine concentration has been associated with vas cular disease and neural tube defects, Methionine synthase is a vitamin B-1 2-dependent enzyme that catalyses the remethylation of homocysteine to meth ionine. Therefore, defects in this enzyme may result in elevated homocystei ne levels. One relatively common polymorphism in the methionine synthase ge ne (D919G) is an A to G transition at bp 2,756, which converts an aspartic acid residue believed to be part of a helix involved in co-factor binding t o a glycine. We have investigated the effect of this polymorphism on plasma homocysteine levels in a working male population (n = 607) in which we pre viously described the relationship of the C677T "thermolabile" methylenetet rahydrofolate reductase (MTHFR) polymorphism with homocysteine levels. We f ound that the methionine synthase D919G polymorphism is significantly (P = 0.03) associated with homocysteine concentration, and the DD genotype contr ibutes to a moderate increase in homocysteine levels across the homocystein e distribution (OR = 1.58, DD genotype in the upper half of the homocystein e distribution, P = 0.006). Unlike thermolabile MTHFR, the homocysteine-ele vating effects of the methionine synthase polymorphism are independent of f olate and B-12 levels; however, the DD genotype has a larger homocysteine-e levating effect in individuals with low Bg levels. This polymorphism may, t herefore, make a moderate, but significant, contribution to clinical condit ions that are associated with elevated homocysteine. Genet. Epidemiol. 17:2 98-309, 1999. (C) 1999 Wiley-Liss, Inc.