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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #165357
Title: EFFECTS OF POLYMORPHISM OF METHIONINE SYNTHASE AND METHIONINE SYNTHASE REDUCTASE ON TOTAL PLASMA HOMOCYSTEINE IN THE NHLBI FAMILY HEART STUDY

Author
item JACQUES, PAUL - TUFTS-HNRCA
item BOSTOM, ANDREW - MEMORIAL HOSPITAL OF RI
item SELHUB, JACOB - TUFTS-HNRCA
item RICH, SHARRON - BOSTON UNIVERSITY
item ELLISON, CURTIS - BOSTON UNIVERSITY
item ECKFELDT, JOHN - UNIVERSITY OF MINNESOTA
item GRAVEL, ROY - UNIVERSITY OF CALGARY
item ROZEN, RIMA - MCGILL UNIVERSITY

Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/14/2002
Publication Date: 1/1/2003
Citation: Jacques, P.F., Bostom, A.G., Selhub, J., Rich, S., Ellison, C.R., Eckfeldt, J., Gravel, R., Rozen, R. 2003. Effects of polymorphism of methionine synthase and methionine synthase reductase on total plasma homocysteine in the NHLBI family heart study. Atherosclerosis. 166:49-55.

Interpretive Summary: The elevation of circulating homocysteine levels is associated with an increased risk of vascular disease. The metabolism of homocysteine requires contribution of a number of enzyme pathways. A critical pathway converts the homocysteine to the amino acid methionine by adding a methyl group to it. We previously identified a common mutation in the gene for the enzyme methylenetetrahydrofolate reductase, which provides the methyl group to homocysteine. This mutation results in an enzyme with lower activity and elevated homocysteine levels. The possibility that mutations in other enzymes involved in the metabolism of homocysteine might also be associated with mild hyperhomocysteinemia led us to examine two enzymes involved in the synthesis of methionine from homocysteine synthase gene (MTR) mutation is an A to G substitution, at base pair 2756 (A2756G). The methionine synthase reductase gene (MTRR) mutation is an A to G substitution at the base pair 66 (A66G). To determine if these mutations were associated with mild hyperhomocysteinemia, we investigated homocysteine levels in subjects from the NHLBI Family Heart Study. MTR and MTRR genotype data were available for 677 and 562 subjects, respectively. The homocysteine levels were unrelated to the MTR or MTRR mutations. There was no significant interaction between MTR and MTRR mutations or between these mutations and any of the vitamins involved in homocysteine metabolism. This study provides no evidence that these common MTR and MTRR mutations are associated with alterations in plasma homocysteine metabolism.

Technical Abstract: The metabolism of homocysteine requires contributions of several enzymes and vitamin cofactors. Common variants have been identified in two enzymes involved in homocysteine metabolism, methionine synthase and methione synthase reductase. Methionine synthase catalyzes the remethylation of homocysteine to form methionine and methionine synthase reductase is required for the reductive activation of the coblamin- dependent methionine synthase. The methionine synthase gene (MTR) mutation is an A to G substitution, 2756 A to G, which converts an aspartate to a glycine codon. The methionine synthase reductase gene (MTRR) mutation is an A to G susbstitution, 66 A to G, that converts an isoleucine to a methionine residue. To determine if thse polymorphisms were associated with mild hyperhomocysteinemia, we investigated subjects from the NHLBI Family Heart Study. Total plasma homcysteine levels were determined after an overnight fast and after a four-hour methionine-load test. MTR and MTRR genotype data were available for 677 and 562 subjects, respectively. The genometric 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 levels. This study provides no evidence that these common MTR and MTRR mutations are associated with alterations in plasma homocysteine.