The ALDH2 Glu504Lys polymorphism is associated with coronary artery disease in Han Chinese: Relation with endothelial ADMA levels
The ALDH2 Glu504Lys polymorphism is associated with coronary artery disease in Han Chinese: Relation with endothelial ADMA levels
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ALDH2 Glu504Lys 多态性与汉族冠心病相关：与内皮 ADMA 水平的关系
DOI：
10.1016/j.atherosclerosis.2010.03.030
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发表时间：
2010-08-01
期刊：
影响因子：
5.3
通讯作者：
Chen, Xiao-Ping
中科院分区：
文献类型：
--
作者：
Guo, Yi-Jie;Chen, Lei;Chen, Xiao-Ping
目的：研究线粒体醛脱氢酶（ALDH2） Glu504Lys （rs671或ALDH2*2）多态性与冠状动脉疾病（CAD）的关系，并试图阐明这种关系的机制。方法：对417例CAD患者和448例年龄和性别匹配的对照组进行ALDH2 rs671多态性基因分型。所有参与者均为汉族。从11条人脐带中分离的人脐静脉内皮细胞（HUVECs）进行基因分型、培养并暴露于血管紧张素II (Ang II, 10（-7) - 10(-5) mol/L）中。实时荧光定量PCR检测二甲基精氨酸二甲氨基水解酶1 (DDAH1) mRNA表达水平。采用高效液相色谱-质谱法（HPLC-MS）测定培养基和细胞裂解物中不对称二甲基精氨酸（ADMA）含量。结果：冠心病患者携带ALDH2 rs671 A等位基因（GA + AA）的频率（47.5%）显著高于对照组（35.0%,p = 0.0002）。校正潜在混杂因素后，在整个研究队列中，rs671 A等位基因携带者患CAD的比值比（OR）为1.85(95%可信区间[CI]: 1.38-2.49, p = 0.00005)，在不饮酒者中为1.95 （95% CI: 1.40-2.70, p = 0.00007）。在非饮酒对照中，纯合子rs671 AA基因型与rs671 GG基因型相比，高密度脂蛋白胆固醇（HDL-C）浓度显著降低（p = 0.015）。rs671 G等位基因纯合子的HUVEC细胞与杂合子的GA细胞相比，DDAH1 mRNA表达显著升高（p < 0.05），细胞内ADMA水平显著降低（p < 0.05）。在纯合子GG细胞中，高浓度的Ang II （10(-5) mol/L）降低了DDAH1 mRNA的表达，增加了细胞内ADMA浓度。结论：ALDH2 rs671多态性与冠心病相关，可能通过影响HDL-C水平和内皮ADMA水平。2010爱思唯尔爱尔兰有限公司版权所有。
Objectives: We studied the association between mitochondrial aldehyde dehydrogenase (ALDH2) Glu504Lys (rs671 or ALDH2*2) polymorphism and coronary artery disease (CAD), and sought to clarify the mechanisms underlying this association.Methods: The ALDH2 rs671 polymorphism was genotyped in 417 CAD patients and 448 age-and gender-matched controls. All participants were Han Chinese. Human umbilical vein endothelial cells (HUVECs) isolated from 11 human umbilical cords were genotyped, cultured, and exposed to angiotensin II (Ang II, 10(-7) - 10(-5) mol/L). Dimethylarginine dimethylaminohydrolase 1 (DDAH1) mRNA expression levels were determined by real-time PCR. Levels of asymmetric dimethylarginine (ADMA) in culture media and cell lysates were determined by high performance liquid chromatography-mass spectrometry (HPLC-MS).Results: The frequency of carriers of the ALDH2 rs671 A allele (GA + AA) was significantly higher in patients with CAD (47.5%) than in controls (35.0%, p = 0.0002). After adjustment for potential confounders, the odds ratio (OR) for CAD for carriers of the rs671 A allele was 1.85 (95% confidence interval [CI]: 1.38-2.49, p = 0.00005) in the entire study cohort, and 1.95 (95% CI: 1.40-2.70, p = 0.00007) in non-drinkers. In non-drinking controls, the homozygous rs671 AA genotype was associated with significantly lower high-density lipoprotein cholesterol (HDL-C) concentrations compared with rs671 GG homozygotes (p = 0.015). HUVEC cells homozygous for the G allele of rs671 showed a significantly higher DDAH1 mRNA expression and lower intracellular ADMA levels compared with heterozygous GA cells (p < 0.05, respectively). In homozygous GG cells, high concentrations of Ang II (10(-5) mol/L) decreased DDAH1 mRNA expression and increased intracellular ADMA concentrations.Conclusions: The rs671 polymorphism of ALDH2 is associated with CAD in Han Chinese, possibly by influencing HDL-C levels and endothelial ADMA levels. (C) 2010 Elsevier Ireland Ltd. All rights reserved.