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Interactions among polymorphisms in folate-metabolizing genes and serum total homocysteine concentrations in a healthy elderly population^1,2,3

¹ From the Department of Internal Medicine, University of California, Davis, Davis, CA (AMD and CHH), and the Clinical Trial Service Unit and Epidemiological Studies Unit (RC and JB) and the University Division of Clinical Gerontology (JGE), Nuffield Department of Clinical Medicine, Radcliffe Infirmary, University of Oxford, Oxford, United Kingdom

Background: Homocysteine concentrations are influenced by vitamin status and genetics, especially several polymorphisms in folate-metabolizing genes.

Objective: We examined the interactions and associations with serum total homocysteine (tHcy) and folate concentrations of polymorphisms in the following folate-metabolizing genes: methylenetetrahydrofolate reductase (MTHFR), reduced folate carrier 1 (RFC1), and glutamate carboxypeptidase II (GCPII).

Design: Healthy volunteers (436 men and 606 women; mean age: 77.9 y) were randomly selected from among residents of Oxford, United Kingdom. We determined the individual effects and interactions of the MTHFR 677CT, MTHFR 1298AC, RFC1 80GA, and GCPII 1561CT polymorphisms on serum tHcy and folate concentrations.

Results: Subjects with the MTHFR 677TT genotype had higher serum tHcy concentrations than did those with the MTHFR 677CC genotype (P < 0.001), and this effect was greater in subjects with low serum folate status (P for interaction = 0.026). The MTHFR 1298AC, RFC1 80GA, and GCPII 1561CT polymorphisms had no individual effects on serum tHcy or folate concentrations. There was no interactive effect of the MTHFR 677CT and MTHFR 1298AC polymorphisms on tHcy concentrations. An interaction (P = 0.05) was observed between the MTHFR 677TT and RFC1 80GG genotypes, whereby persons with this genotype combination had a mean (±SEM) serum tHcy concentration (18.5 ± 1.2 µmol/L) that was 5.1 µmol/L greater than the mean value of 13.4 ± 0.2 µmol/L for the whole population.

Conclusions: Folate and tHcy concentrations were not affected individually by the MTHFR 1298AC, RFC1 80GA, or GCPII 1561CT polymorphisms or by combinations of the MTHFR 677CT and MTHFR 1298AC genotypes. An interaction between the MTHFR 677TT and RFC1 80GG genotypes was observed whereby persons with this combination had higher serum tHcy.

Key Words: Serum folate • serum total homocysteine • methylenetetrahydrofolate reductase 677CT polymorphism • methylenetetrahydrofolate reductase 1298AC polymorphism • reduced folate carrier 1 80GA polymorphism • glutamate carboxypeptidase II 1561CT polymorphism • elderly

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