Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism

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: methylenetetrahy- drofolate 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 (BHTM) c.716G > A (known as 742G > A; p.Arg239Gln); cystathionine P-synthase (CBS) c-844_845ins68 and c.699C > T (p.Tyr233Tyr); transcobalamin,11 (TCN2) c.67A > G (p.Ile23Val) and c.776C > G (p.Pro259Arg); reduced folate carrier-1 (SLC19Al) c.80G>A (p.Arg27His); and paraoxonase-1 (PON1) c.163T > A (p.Leu55Met) and c.575A > G (p.Glnl92Arg). 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 (13MG), 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.