Spiecker Martin, Darius Harald, Hankeln Thomas, Soufi Muhidien, Sattler Alexander M, Schaefer Jürgen R, Node Koichi, Börgel Jan, Mügge Andreas, Lindpaintner Klaus, Huesing Anika, Maisch Bernhard, Zeldin Darryl C, Liao James K
Department of Medicine II/Cardiology, St. Josef-Hospital, University of Bochum, Gudrunstr 56, 44791 Bochum, Germany.
Circulation. 2004 Oct 12;110(15):2132-6. doi: 10.1161/01.CIR.0000143832.91812.60. Epub 2004 Oct 4.
Cytochrome P450 (CYP) 2J2 is expressed in the vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs). The EETs are potent endogenous vasodilators and inhibitors of vascular inflammation. However, it is not known whether genetic polymorphisms of CYP2J2 are associated with increased cardiovascular risks.
All 9 exons of the CYP2J2 gene and its proximal promoter were sequenced in 132 patients to identify potential variants. Functional consequence of a single nucleotide polymorphism (SNP) in the promoter of CYP2J2 was further evaluated by use of transcription factor-binding and reporter assays. A total of 17 polymorphisms were identified. One of the most relevant polymorphisms in terms of frequency and functional importance is located at -50 (G-50T) in the proximal promoter of CYP2J2. Screening of 289 patients with coronary artery disease and 255 control subjects revealed 77 individuals with the G-50T SNP (17.3% of coronary artery disease patients, 10.6% of control subjects; P=0.026). The association of the G-50T polymorphism remained significant after adjustment for age, gender, and conventional cardiovascular risk factors (OR, 2.23; 95% CI, 1.04 to 4.79). The G-50T mutation resulted in the loss of binding of the Sp1 transcription factor to the CYP2J2 promoter and resulted in a 48.1+/-2.4% decrease in CYP2J2 promoter activity (P<0.01). Plasma concentrations of stable EET metabolites were significantly lower in individuals with the G-50T SNP.
A functionally relevant polymorphism of the CYP2J2 gene is independently associated with an increased risk of coronary artery disease.
细胞色素P450（CYP）2J2在血管内皮中表达，可将花生四烯酸代谢为具有生物活性的环氧二十碳三烯酸（EETs）。EETs是强效的内源性血管舒张剂和血管炎症抑制剂。然而，CYP2J2的基因多态性是否与心血管风险增加相关尚不清楚。
对132例患者的CYP2J2基因的所有9个外显子及其近端启动子进行测序，以鉴定潜在变异。通过转录因子结合和报告基因检测进一步评估CYP2J2启动子中单个核苷酸多态性（SNP）的功能后果。共鉴定出17种多态性。就频率和功能重要性而言，最相关的多态性之一位于CYP2J2近端启动子的-50（G-50T）处。对289例冠心病患者和255例对照受试者进行筛查，发现77例携带G-50T SNP（冠心病患者中占17.3%，对照受试者中占10.6%；P=0.026）。在调整年龄、性别和传统心血管危险因素后，G-50T多态性的相关性仍然显著（OR，2.23；95%CI，1.04至4.79）。G-50T突变导致Sp1转录因子与CYP2J2启动子的结合丧失，并导致CYP2J2启动子活性降低48.1±2.4%（P<0.01）。携带G-50T SNP的个体中稳定EET代谢物的血浆浓度显著降低。
CYP2J2基因的一个功能相关多态性与冠心病风险增加独立相关。
