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 1 (RFC1), and glutamate carboxypeptidase II (GCPII).


METHODS
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 80G-->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 micromol/L) that was 5.1 micromol/L greater than the mean value of 13.4 +/- 0.2 micromol/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.
Devlin
Angela M
AM
Department of Internal Medicine, University of California, Davis, Davis, CA, USA. angela.devlin@ubc.ca
Clarke
Robert
R
Birks
Jacqueline
J
Evans
John Grimley
JG
Halsted
Charles H
CH
D000368:Aged; D000369:Aged, 80 and over; D004739:England; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D043425:Glutamate Carboxypeptidase II / Q000235:genetics*; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D011110:Polymorphism, Genetic
D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D043425:Glutamate Carboxypeptidase II