Effects of polymorphisms of methionine synthase and methionine synthase reductase on total plasma homocysteine in the NHLBI Family Heart Study

Paul F. Jacques, Andrew G. Bostom, Jacob Selhub, Sharron Rich, R. Curtis Ellison, John H. Eckfeldt, Roy A. Gravel, Rima Rozen

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86 Scopus citations

Abstract

The metabolism of homocysteine requires contributions of several enzymes and vitamin cofactors. Earlier studies identified a common polymorphism of methylenetetrahydrofolate reductase that was associated with mild hyperhomocysteinemia. Common variants of two other enzymes involved in homocysteine metabolism, methionine synthase and methionine synthase reductase, have also been identified. Methionine synthase catalyzes the remethylation of homocysteine to form methionine and methionine synthase reductase is required for the reductive activation of the cobalamin-dependent methionine synthase. The methionine synthase gene (MTR) mutation is an A to G substitution, 2756A→G, which converts an aspartate to a glycine codon. The methionine synthase reductase gene (MTRR) mutation is an A to G substitution, 66A→G, that converts an isoleucine to a methionine residue. To determine if these polymorphisms were associated with mild hyperhomocysteinemia, we investigated subjects from two of the NHLBI Family Heart Study field centers, Framingham and Utah. Total plasma homocysteine concentrations were determined after an overnight fast and after a 4-h methionine load test. MTR and MTRR genotype data were available for 677 and 562 subjects, respectively. The geometric mean fasting homocysteine was unrelated to the MTR or MTRR genotype categories (AA, AG, GG). After a methionine load, a weak positive association was observed between change in homocysteine after a methionine load and the number of mutant MTR alleles (P-trend=0.04), but this association was not statistically significant according to the overall F-statistic (P=0.12). There was no significant interaction between MTR and MTRR genotype or between these genotypes and any of the vitamins with respect to homocysteine concentrations. This study provides no evidence that these common MTR and MTRR mutations are associated with alterations in plasma homocysteine.

Original languageEnglish (US)
Pages (from-to)49-55
Number of pages7
JournalAtherosclerosis
Volume166
Issue number1
DOIs
StatePublished - Jan 1 2003

Bibliographical note

Funding Information:
The authors would like to acknowledge the invaluable effort of Greta Lee Splansky and Jan Skuppin and their associates in the collection of data during this project. The authors are also grateful for the excellent technical assistance provided by Nelly Sabbaghian and Qing Wu and the statistical and programming support provided by Gail Rogers. This work has been supported with funds from the Canadian Institutes of Health Research Group in Medical Genetics no. GR-13297, the National Institutes of Health/National Heart, Lung and Blood Institute grant number HL58955-01 and number 53-3K06-01 and contract number N01-HC-25106 (The Family Genetics Studies of Cardiovascular Disease), and the US Department of Agriculture under agreement No. 58-1950-9-001. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the US Department of Agriculture.

Keywords

  • B vitamins
  • Epidemiologic study
  • Homocysteine
  • Methionine synthase
  • Methionine synthase reductase

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