The ALDH2 Glu504Lys polymorphism is associated with coronary artery disease in Han Chinese: Relation with endothelial ADMA levels.
OBJECTIVE
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.
Guo
Yi-Jie
YJ
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, 110# Xiangya Road, Changsha, Hunan 410078, China.
Chen
Lei
L
Bai
Yong-Ping
YP
Li
Ling
L
Sun
Ji
J
Zhang
Guo-Gang
GG
Yang
Tian-Lun
TL
Xia
Jian
J
Li
Yuan-Jian
YJ
Chen
Xiao-Ping
XP
D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D002681:China; D003324:Coronary Artery Disease / Q000208:ethnology / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000235:genetics*; D006801:Humans; D008239:Lysine / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012307:Risk Factors
D018698:Glutamic Acid; C018524:N,N-dimethylarginine; D001120:Arginine; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D008239:Lysine