title: Functional inference of the methylenetetrahydrofolate reductase 677C > T and 1298A > C polymorphisms from a large-scale epidemiological study.
abstract: Two functional single nucleotide polymorphisms, 677C > T and 1298A > C have been described for the methylenetetrahydrofolate (MTHFR) gene. Both are associated with reduced enzyme activity in vitro. For the 677T, but not the 1298C allele, significantly lower serum folate and higher plasma total homocysteine (tHcy) have been reported. We genotyped 10,034 middle-aged (50-64 years old) subjects and measured serum folate and tHcy. Within strata of 677 genotypes, 1,298 genotypes had significantly different serum folate and tHcy (P < or = 0.03 for all comparisons). Each additional 1298C allele reduced mean serum folate and increased mean tHcy, by (on average) 4.5 and 3.0%, respectively. In comparison, within strata of 1,298 genotypes, the increase from no, to one 677T-allele reduced serum folate and increased tHcy by, 7.1 and 6.3%, respectively. Lowest serum folate and highest tHcy level was found for the 677TT/1298AA genotype. The difference in tHcy was significantly larger at low folate than at high folate when genotypes 677TT/1298AA and 677CT/1298AA, 677CT/1298AC and 677CC/1298AC, and genotypes 677CT/1298AC and 677CT/1298AA were compared. We interpreted these data in the context of a model of the MTHFR enzyme that describes the enzyme as a dimer that mainly exist in six different configurations. The model reconciled the observed phenotypic effects of the 677/1,298 combination genotypes with previous in vitro measurements, and identified enzyme configurations that are sensitive to low folate levels. In conclusion, this report demonstrates functional inference of the MTHFR 677 C > T and 1,298 A > C polymorphisms from a large-scale epidemiological study.
authors.affiliation: LOCUS for Homocysteine and Related Vitamins, Department of Internal Medicine, Pharmacology Section, University of Bergen, Armauer Hansens hus, 5021 Bergen, Norway. arve.ulvik@farm.uib.no
authors.forename: Arve
authors.initials: A
authors.lastname: Ulvik
authors.forename: Per M
authors.initials: PM
authors.lastname: Ueland
authors.forename: Ase
authors.initials: A
authors.lastname: Fredriksen
authors.forename: Klaus
authors.initials: K
authors.lastname: Meyer
authors.forename: Stein Emil
authors.initials: SE
authors.lastname: Vollset
authors.forename: Geir
authors.initials: G
authors.lastname: Hoff
authors.forename: Jørn
authors.initials: J
authors.lastname: Schneede
mesh_terms: D000227:Adenine Nucleotides / Q000235:genetics; D003597:Cytosine Nucleotides / Q000235:genetics; D016021:Epidemiologic Studies; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000235:genetics; D005838:Genotype; D006710:Homocysteine / Q000097:blood / Q000235:genetics; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013942:Thymine Nucleotides / Q000235:genetics
chemical_list: D000227:Adenine Nucleotides; D003597:Cytosine Nucleotides; D013942:Thymine Nucleotides; D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)