Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism
Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism
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DOI：
10.1002/humu.20522
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发表时间：
2007-09-01
期刊：
影响因子：
3.9
通讯作者：
Schneede, Jorn
中科院分区：
文献类型：
--
作者：
Fredriksen, Ase;Meyer, Klaus;Schneede, Jorn
已经确定了几个参与单碳代谢的基因多态性。报道的代谢表型通常是基于提供不一致结果的小型研究。这项基于10601个人群样本的大规模研究是为了调查一组生化参数与一种碳代谢相关的遗传变异之间的关系。测定血清/血浆中总同型半胱氨酸（tHcy）、叶酸、维生素B-12（钴胺素）、甲基丙二酸（MMA）、维生素B-2（核黄素）、维生素B-6 （PLP）、胆碱、甜菜碱、二甲基甘氨酸（DMG）、胱氨酸、半胱氨酸蛋氨酸和肌酐的浓度。所有受试者对13种常见多态性进行基因分型：亚甲基四氢叶酸还原酶（MTHFR） C . 665c > T（称为677C > T; p.Ala222Val）和C . 1286a > C（称为1298A > C; p.Glu429Ala）；蛋氨酸合成酶（MTR） c.2756A > G (p.Asp919Gly)；蛋氨酸合成酶还原酶（MTRR） c.66A > G (p.Ile22Met)；亚甲基四氢叶酸脱氢酶（MTHFD1） c.1958G > A (p.Arg653Gln)；甜菜碱同型半胱氨酸甲基转移酶（BHTM） c.716G > A（称为742G > A; p.Arg239Gln）；半胱甘氨酸p -合成酶（CBS） c-844_845ins68和c. 699c> T (p.Tyr233Tyr)；转钴胺素，11 (TCN2) c.67A > G （p.p ile23val）和c.776C > G (p.p pro259arg)；还原叶酸载体1 (SLC19Al) c.80G>A (p.Arg27His)；对氧磷酶-1 (PON1) c.163T > A （p.Leu55Met）和c.575A > G （p.Glnl92Arg）。研究了这13个多态性的代谢特征，包括所测的维生素和代谢物。我们证实MTHFR c.665C > T与tHcy和叶酸有很强的相关性，但根据其他基因多态性也观察到代谢物浓度的显著变化（P < 0.01）。这些包括MTHFR C . 1286a > C（与tHcy，叶酸和甜菜碱相关），MTR C . 2756a b> G (tHcy), BHMT C . 716g b> A (13MG), CBS C .844_845ins68 （tHcy，甜菜碱），CBS C . 699c b> T （tHcy，甜菜碱，半胱甘氨酸）和TCN2 C . 776c > G （MMA）。其他被调查的多态性未发现关联。
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.