对与一碳代谢相关的13种基因多态性进行基于大规模人群的代谢表型分析。

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

作者信息

Fredriksen Ase, Meyer Klaus, Ueland Per Magne, Vollset Stein Emil, Grotmol Tom, Schneede Jørn

机构信息

LOCUS for Homocysteine and Related Vitamins, University of Bergen, Bergen, Norway.

出版信息

Hum Mutat. 2007 Sep;28(9):856-65. doi: 10.1002/humu.20522.

DOI:10.1002/humu.20522

PMID:17436311

Abstract

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 beta-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.

摘要

已鉴定出参与一碳代谢的多个基因多态性。所报道的代谢表型通常基于一些小型研究，其结果并不一致。本研究对10601份基于人群的样本进行了大规模研究，以调查一组生化参数与一碳代谢相关基因变异之间的关联。测定了血清/血浆中总同型半胱氨酸（tHcy）、叶酸、维生素B12（钴胺素）、甲基丙二酸（MMA）、维生素B2（核黄素）、维生素B6（PLP）、胆碱、甜菜碱、二甲基甘氨酸（DMG）、胱硫醚、半胱氨酸、蛋氨酸和肌酐的浓度。对所有受试者进行了13种常见多态性的基因分型：亚甲基四氢叶酸还原酶（MTHFR）c.665C>T（即677C>T；p.Ala222Val）和c.1286A>C（即1298A>C；p.Glu429Ala）；蛋氨酸合酶（MTR）c.2756A>G（p.Asp919Gly）；蛋氨酸合酶还原酶（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（BHMT）c.716G>A（即742G>A；p.Arg239Gln）；胱硫醚β合酶（CBS）c.844_845ins68和c.699C>T（p.Tyr233Tyr）；转钴胺素II（TCN2）c.67A>G（p.Ile23Val）和c.776C>G（p.Pro259Arg）；还原型叶酸载体1（SLC19A1）c.80G>A（p.Arg27His）；对氧磷酶1（PON1）c.163T>A（p.Leu55Met）和c.575A>G（p.Glnl92Arg）。针对这13种多态性，研究了所测维生素和代谢物的代谢谱。我们证实了MTHFR c.665C>T与tHcy和叶酸之间的强关联，但也观察到根据其他基因多态性代谢物浓度有显著（P<0.01）变化。这些包括MTHFR c.1286A>C（与tHcy、叶酸和甜菜碱有关）、MTR c.2756A>G（tHcy）、BHMT c.716G>A（DMG）、CBS c.844_845ins68（tHcy、甜菜碱）、CBS c.699C>T（tHcy、甜菜碱、胱硫醚）和TCN2 c.776C>G（MMA）。对于所研究的其他多态性未观察到关联。