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Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients.
- Source :
-
Human genetics [Hum Genet] 2002 Jul; Vol. 111 (1), pp. 1-8. Date of Electronic Publication: 2002 Jun 19. - Publication Year :
- 2002
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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.
- Subjects :
- Aged
Animals
Coronary Artery Disease metabolism
Diabetes Mellitus, Type 2 metabolism
Female
Genetic Predisposition to Disease
Heme Oxygenase (Decyclizing) metabolism
Heme Oxygenase-1
Humans
Luciferases metabolism
Male
Membrane Proteins
Muscle, Smooth, Vascular metabolism
Polymerase Chain Reaction
Promoter Regions, Genetic
Rats
Thiobarbituric Acid Reactive Substances metabolism
Transfection
Coronary Artery Disease genetics
Diabetes Mellitus, Type 2 genetics
Heme Oxygenase (Decyclizing) genetics
Microsatellite Repeats genetics
Polymorphism, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 0340-6717
- Volume :
- 111
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 12136229
- Full Text :
- https://doi.org/10.1007/s00439-002-0769-4