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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #165916
Title: AGE AND GENDER AFFECT THE RELATION BETWEEN METHYLENETETRAHYDROFOLATE REDUCTASE C677T GENOTYPE AND FASTING PLASMA HOMOCYSTEINE CONCENTRATIONS IN THE FRAMINGHAM OFFSPRING STUDY COHORT

Author
item RUSSO, GIUSEPPINA - UNIVERSITY OF MESSINA
item FRISO, SIMONETTA - UNIVERSITY OF MESSINA
item JACQUES, PAUL - TUFTS-HNRCA
item ROGERS, GAIL - TUFTS-HNRCA
item CUCINOTTA, DOMENICO - UNIVERSITY OF MESSINA
item WILSON, PETER - FRAMINGHAM HEART STUDY
item ORDOVAS, JOSE - TUFTS-HNRCA
item ROSENBERG, IRWIN - TUFTS-HNRCA
item SELHUB, JACOB - TUFTS-HNRCA

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/1/2003
Publication Date: 11/1/2003
Citation: Russo, G.T., Friso, S., Jacques, P.F., Rogers, G., Cucinotta, D., Wilson, P.W., Ordovas, J.M., Rosenberg, I.H., Selhub, J. 2003. Age and gender affect the relation between methylenetetrahydrofolate reductase c677t genotype and fasting plasma homocysteine concentrations in the framingham offspring study cohort. Journal of Nutrition. 133:3416-3421.

Interpretive Summary: Elevated circulating homocysteine is associated with an increased risk of cardiovascular disease (CVD). The maintenance of low homocysteine levels requires the contribution of various enzyme pathways as well as folate, and vitamins B12 and B6, which serve as substrates and cofactors in these enzyme pathways. One critical pathway converts the homocysteine to the amino acid methionine by adding a methyl group to it. A common mutation in the gene for the enzyme methylenetetrahydrofolate reductase (MTHFR), which provides the methyl group in the form of methyltetrahydrofolate to homocysteine, results in an enzyme with lower activity and elevated homocysteine levels. However, the elevated homocysteine levels are only seen when those with this mutation do not have sufficient circulating levels of folate. Elevated homocysteine levels are not seen when those with the mutation have adequate folate status. The molecular defect responsible for this MTHFR genetic variant is a cytosine (C) to thymidine (T) transition at nucleotide 677 (C677T) in the MTHFR gene. This, in turn, results in an alanine to valine substitution in the folate-binding site of the enzyme. We investigated the possibility that the relationship between the MTHFR C677T mutation and elevated homocysteine levels is affected by gender and age because homocysteine levels are consistently higher in men than in women, and increase with age. We demonstrated that among those with lower folate status, the mutation was only associated with higher homocysteine levels in younger (<55 y) males. The mutation did not affect circulating homocysteine levels in women or older men. This may explain, in part, the inconsistent relation between this MTHFR mutation and CVD risk.

Technical Abstract: The C677T variant of methylenetetrahydrofolate reductase, a key enzyme in remethylation of homocysteine to methionine, is the most frequent genetic cause of mild hyperhomocysteinemia, especially in subjects with low folate status. However, little is known about the influence of subject characteristics, such as age and sex, on the relation between the C677T MTHFR polymorphism and fasting total homocysteine (tHcy) concentrations. The aim of the present study was to explore whether age and gender, together with folate status, affect the association between the common C677T variation at the MTHFR gene locus and mild hyperhomocysteinemia. The C677T genotype was determined in 871 male and 949 female participants in the 5th examination of the Framingham Offspring Study. The allelic distribution was not different from the Hardy-Weinberg equilibrium, with an overall TT homozygous frequency comparable in men and women (14%). Geometric mean tHcy was 15% higher in men than in women (P<0.0001), and women had significantly higher folate plasma levels (P=0.0001). Geometric mean tHcy was significantly higher in TT homozygous participants (P=0.001) than in those with the CC and CT genotypes in those with plasma folate below the sample median (12.5 nmol/L), but not in those with higher folate status. Because of a significant age and sex interaction (P=0.02), we further stratified by age and sex, and observed that the association between genotype and tHcy was confined to men aged < 55 years (P<0.001). In conclusion, we demonstrated that age and sex modify the contribution of the MTHFR C677T mutation to fasting tHcy concentrations.