甲硫氨酸合成酶基因多态性A2756G与血栓栓塞事件的易感性及B族维生素/硫醇代谢改变有关。

Methionine synthase polymorphism A2756G is associated with susceptibility for thromboembolic events and altered B vitamin/thiol metabolism.

作者信息

Yates Zoe, Lucock Mark

机构信息

University of Leeds, West Yorkshire, United Kingdom.

出版信息

Haematologica. 2002 Jul;87(7):751-6; discussion 756.

PMID:12091127

Abstract

BACKGROUND AND OBJECTIVES

Vitamin B12 dependent methionine synthase (MS) regulates de novo production of methionine from homocysteine (Hcy). Since moderate elevations in Hcy are considered vasculotoxic, we examined a common variant (A2756G-MS) of the gene coding for this enzyme as a risk for thromboembolism.

DESIGN AND METHODS

We investigated A2756G-MS and folate/thiol status in 51 individuals who had experienced a thromboembolic event (TE) and 95 subjects being treated for non-thromboembolic (NTE) vascular problems.

RESULTS

The prevalence of the mutant G allele was lower in TE subjects than in controls, indicating a protective role for this base substitution (OR 0.39; 95%CI 0.20-0.78; p=0.010). Consistent with an advantage conferred by this allele, heterozygotes had generally lower levels of Hcy and glutathione (GSH), and higher levels of B-vitamins than wildtypes. The OR for the wildtype having an increased risk for TE was 2.32 (95%CI 1.06-5.08). Additionally, as might be predicted, TE-wildtypes had elevated GSH levels compared to corresponding NTE-wildtypes (p=0.004) - a likely response to oxidative stress. NTE subjects showed a dramatic reduction in Hcy between wildtype and heterozygote (p=0.017), and again between recessive and heterozygote genotypes (p=0.002). The same pattern, although not significant, occurred in TE subjects. The similarity in Hcy between clinical groups for each genotype raises questions on the etiological role of Hcy in TE. The functional relationship between enzyme variant and its B12-cofactor may be of more interest, since the polymorphic site occurs near the B12-binding domain, and our results indicate wildtype-TE subjects have a much lower level of vitamin B12 than heterozygote-TE subjects (p=0.0019). This effect is attenuated in NTE subjects.

INTERPRETATION AND CONCLUSIONS

. A2756G-MS may protect against a thromboembolic event. The role of Hcy remains unclear.

摘要

背景与目的

维生素B12依赖型蛋氨酸合酶（MS）调节同型半胱氨酸（Hcy）从头合成蛋氨酸的过程。鉴于Hcy适度升高被认为具有血管毒性，我们研究了编码该酶的基因的一种常见变异（A2756G-MS）作为血栓栓塞的风险因素。

设计与方法

我们调查了51例发生血栓栓塞事件（TE）的个体以及95例因非血栓栓塞性（NTE）血管问题接受治疗的受试者的A2756G-MS以及叶酸/硫醇状态。

结果

TE受试者中突变型G等位基因的患病率低于对照组，表明这种碱基替换具有保护作用（比值比0.39；95%置信区间0.20 - 0.78；p = 0.010）。与该等位基因赋予的优势一致，杂合子的Hcy和谷胱甘肽（GSH）水平通常低于野生型，而B族维生素水平高于野生型。野生型发生TE风险增加的比值比为2.32（95%置信区间1.06 - 5.08）。此外，正如预期的那样，与相应的NTE野生型相比，TE野生型的GSH水平升高（p = 0.004）——这可能是对氧化应激的一种反应。NTE受试者中，野生型与杂合子之间的Hcy显著降低（p = 0.017），隐性和杂合子基因型之间同样显著降低（p = 0.002）。TE受试者中也出现了相同的模式，尽管不显著。各基因型临床组之间Hcy的相似性引发了关于Hcy在TE中的病因学作用的疑问。酶变异与其B12辅因子之间的功能关系可能更受关注，因为多态性位点位于B12结合域附近，且我们的结果表明野生型TE受试者的维生素B12水平远低于杂合子TE受试者（p = 0.0019）。这种效应在NTE受试者中减弱。