Voetsch Barbara, Jin Richard C, Bierl Charlene, Deus-Silva Leonardo, Camargo Erica C S, Annichino-Bizacchi Joyce M, Handy Diane E, Loscalzo Joseph
Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA 02115, USA.
Stroke. 2008 Feb;39(2):303-7. doi: 10.1161/STROKEAHA.107.490094. Epub 2007 Dec 20.
Plasma glutathione peroxidase (GPx-3) is a major antioxidant enzyme in plasma and the extracellular space that scavenges reactive oxygen species produced during normal metabolism or after oxidative insult. A deficiency of this enzyme increases extracellular oxidant stress, promotes platelet activation, and may promote oxidative posttranslational modification of fibrinogen. We recently identified a haplotype (H(2)) in the GPx-3 gene promoter that increases the risk of arterial ischemic stroke among children and young adults.
The aim of this study is to identify possible relationships between promoter haplotypes in the GPx-3 gene and cerebral venous thrombosis (CVT). We studied the GPx-3 gene promoter from 23 patients with CVT and 123 young controls (18 to 45 years) by single-stranded conformational polymorphism and sequencing analysis.
Over half of CVT patients (52.1%) were heterozygous (H(1)H(2)) or homozygous (H(2)H(2)) carriers of the H(2) haplotype compared with 12.2% of controls, yielding a more than 10-fold independent increase in the risk of CVT (OR=10.7; 95% CI, 2.70 to 42.36; P<0.0001). Among women, the interaction of the H(2) haplotype with hormonal risk factors increased the OR of CVT to almost 70 (P<0.0001).
These findings show that a novel GPx-3 promoter haplotype is a strong, independent risk factor for CVT. As we have previously shown that this haplotype is associated with a reduction in transcriptional activity, which compromises antioxidant activity and antithrombotic benefits of the enzyme, these results suggest that a deficiency of GPx-3 leads to a cerebral venous thrombophilic state.
血浆谷胱甘肽过氧化物酶（GPx - 3）是血浆和细胞外空间中的一种主要抗氧化酶，可清除正常代谢过程中或氧化损伤后产生的活性氧。这种酶的缺乏会增加细胞外氧化应激，促进血小板活化，并可能促进纤维蛋白原的氧化翻译后修饰。我们最近在GPx - 3基因启动子中鉴定出一种单倍型（H(2)），它会增加儿童和年轻成年人动脉缺血性卒中的风险。
本研究的目的是确定GPx - 3基因启动子单倍型与脑静脉血栓形成（CVT）之间可能的关系。我们通过单链构象多态性和测序分析研究了23例CVT患者和123名年轻对照者（18至45岁）的GPx - 3基因启动子。
超过一半的CVT患者（52.1%）是H(2)单倍型的杂合子（H(1)H(2)）或纯合子（H(2)H(2)）携带者，而对照组中这一比例为12.2%，CVT风险独立增加了10倍以上（OR = 10.7；95% CI，2.70至42.36；P < 0.0001）。在女性中，H(2)单倍型与激素风险因素的相互作用使CVT的OR增加到近70（P < 0.0001）。
这些发现表明，一种新的GPx - 3启动子单倍型是CVT的一个强大的独立风险因素。正如我们之前所表明的，这种单倍型与转录活性降低有关，这会损害该酶的抗氧化活性和抗血栓益处，这些结果表明GPx - 3缺乏会导致脑静脉血栓形成倾向状态。
