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Large‐scale population‐based metabolic phenotyping of thirteen genetic polymorphisms related to one‐carbon metabolism
Author(s) -
Fredriksen Åse,
Meyer Klaus,
Ueland Per Magne,
Vollset Stein Emil,
Grotmol Tom,
Schneede Jørn
Publication year - 2007
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20522
Subject(s) - mtrr , methylenetetrahydrofolate reductase , cystathionine beta synthase , methionine synthase , homocysteine , methylmalonic acid , biology , betaine , vitamin b12 , cobalamin , population , homocystinuria , hyperhomocysteinemia , methionine , biochemistry , genotype , amino acid , medicine , gene , environmental health
Several polymorphisms of genes involved in one‐carbon metabolism have been identified. The reported metabolic phenotypes are often based on small studies providing inconsistent results. This large‐scale study of 10,601 population‐based samples was carried out to investigate the association between a panel of biochemical parameters and genetics variants related to one‐carbon metabolism. Concentrations of total homocysteine (tHcy), folate, vitamin B 12 (cobalamin), methylmalonic acid (MMA), vitamin B 2 (riboflavin), vitamin B 6 (PLP), choline, betaine, dimethylglycine (DMG), cystathionine, cysteine, methionine, and creatinine were determined in serum/plasma. All subjects were genotyped for 13 common polymorphisms: methylenetetrahydrofolate reductase ( MTHFR ) c.665C>T (known as 677C>T; p.Ala222Val) and c.1286A>C (known as 1298A>C; p.Glu429Ala); methionine synthase ( MTR ) c.2756A>G (p.Asp919Gly); methionine synthase reductase ( MTRR ) c.66A>G (p.Ile22Met); methylenetetrahydrofolate dehydrogenase ( MTHFD1 ) c.1958G>A (p.Arg653Gln); betaine homocysteine methyltransferase ( BHMT ) c.716G>A (known as 742G>A; p.Arg239Gln); cystathionine β‐synthase ( CBS ) c.844_845ins68 and c.699C>T (p.Tyr233Tyr); transcobalamin‐II ( TCN2 ) c.67A>G (p.Ile23Val) and c.776C>G (p.Pro259Arg); reduced folate carrier‐1 ( SLC19A1 ) c.80G>A (p.Arg27His); and paraoxonase‐1 ( PON1 ) c.163T>A (p.Leu55Met) and c.575A>G (p.Gln192Arg). The metabolic profile in terms of the measured vitamins and metabolites were investigated for these 13 polymorphisms. We confirmed the strong associations of MTHFR c.665C>T with tHcy and folate, but also observed significant (P<0.01) changes in metabolite concentrations according to other gene polymorphisms. These include MTHFR c.1286A>C (associations with tHcy, folate and betaine), MTR c.2756A>G (tHcy), BHMT c.716G>A (DMG), CBS c.844_845ins68 (tHcy, betaine), CBS c.699C>T (tHcy, betaine, cystathionine) and TCN2 c.776C>G (MMA). No associations were observed for the other polymorphisms investigated. Hum Mutat 28(9), 856–865, 2007. © 2007 Wiley‐Liss, Inc.