Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients.
Heme oxygenase is a rate-limiting enzyme in heme degradation, leading to the generation of free iron, biliverdin, and carbon monoxide. Induction of heme oxygenase-1 is implicated in the antioxidant defense mechanism and can modulate vascular function. To test the association of microsatellite polymorphism in the promoter region of human HO-1 gene with the risk of coronary artery disease (CAD) in type 2 diabetic patients, we examined the allele frequencies of (GT) (n) repeats in HO-1 gene in 474 patients with CAD and in 322 controls. A transient-transfection assay with HO-1 promoter/luciferase fusion constructs carrying various lengths of (GT) (n) repeats was performed to explore the regulatory effect of (GT) (n) repeats on HO-1 gene expression in cultured rat aortic smooth muscle cells. Serum thiobarbituric acid-reactive substances (TBARs), a measure of lipid peroxidation, was significantly higher in subjects carrying the L/L genotype (> or =32 repeats). Among type 2 diabetic subjects, the frequencies of the L alleles and proportion of genotypes with L alleles were significantly higher in those with CAD than in those without CAD. The adjusted odds ratio for CAD in type 2 diabetic patients with L alleles was 4.7 (95% confidence interval, 1.9-12.0, P=0.001). Transfection experiments in aortic smooth muscle cells revealed that HO-1 promoter/luciferase fusion constructs containing longer (GT) (n) repeats exhibited lower transcriptional activity. These results imply that the length polymorphism in the HO-1 gene promoter modulate the transcription of the gene in vascular cells. Type 2 diabetics carrying longer (GT) (n) repeats might have higher oxidative stress and increased susceptibility to the development of CAD.
Chen
Ying-Hwa
YH
Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China.
Lin
Shing-Jong
SJ
Lin
Ming-Wei
MW
Tsai
Hui-Ling
HL
Kuo
San-San
SS
Chen
Jaw-Wen
JW
Charng
Min-Ji
MJ
Wu
Tao-Cheng
TC
Chen
Lung-Ching
LC
Ding
Yu-An
YA
Pan
Wen-Harn
WH
Jou
Yuh-Shan
YS
Chau
Lee-Young
LY
D000368:Aged; D000818:Animals; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism; D051547:Heme Oxygenase-1; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D018895:Microsatellite Repeats / Q000235:genetics*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D051381:Rats; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014162:Transfection
D008565:Membrane Proteins; D017392:Thiobarbituric Acid Reactive Substances; D008156:Luciferases; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1