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, Shing Jong Lin, Ming Wei Lin, Hui Ling Tsai, San San Kuo, Jaw Wen Chen, Min Ji Charng, Tao Cheng Wu, Lung Ching Chen, Philip Yu An Ding, Wen Harn Pan, Yuh Shan Jou, Lee Young Chau*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

289 Scopus citations

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 (≥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.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalHuman Genetics
Volume111
Issue number1
DOIs
StatePublished - Jul 2002

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