The ALDH2 Glu504Lys polymorphism is associated with coronary artery disease in Han Chinese: Relation with endothelial ADMA levels

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.