Interactions among polymorphisms in folate-metabolizing genes and serum total homocysteine concentrations in a healthy elderly population

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 I (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 677C -> T, MTHFR 1298A -> C, RFC1 80G -> A, and GCPII 1561C -> T 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 1298A -> C, RFC1 8OG -> A, and GCPII 1561C -> T polymorphisms had no individual effects on serum tHcy or folate concentrations. There was no interactive effect of the MTHFR 677C -> T and MTHFR 1298A -> C 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 mu mol/L) that was 5.1 mu mol/L greater than the mean value of 13.4 +/- 0.2 mu mol/L for the whole population. Conclusions: Folate and tHcy concentrations were not affected individually by the MTHFR 1298A -> C, RFC1 80G -> A, or GCPII 1561C -> T polymorphisms or by combinations of the MTHFR 677C -> T and MTHFR 1298A -> C genotypes. An interaction between the MTHFR 677TT and RFC1 80GG genotypes was observed whereby persons with this combination had higher serum tHcy.