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Comparative Study
. 2002 Jul;111(1):1-8.
doi: 10.1007/s00439-002-0769-4. Epub 2002 Jun 19.

Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients

Ying-Hwa Chen  1 , Shing-Jong Lin, Ming-Wei Lin, Hui-Ling Tsai, San-San Kuo, Jaw-Wen Chen, Min-Ji Charng, Tao-Cheng Wu, Lung-Ching Chen, Yu-An Ding, Wen-Harn Pan, Yuh-Shan Jou, Lee-Young Chau
Affiliations
Comparative Study

Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients

Ying-Hwa Chen et al. Hum Genet. 2002 Jul.

Abstract

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.

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