Serum Bilirubin and Ferritin Levels Link Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic Patients

Abstract

OBJECTIVE: Heme oxygenase (HO) leads to the generation of free iron, carbon monoxide, and bilirubin. A length polymorphism of GT repeats in the promoter of human HO-1 gene has been shown to modulate gene transcription. The aim of this study was to assess the association of the length of (GT)(n) repeats in the HO-1 gene promoter with serum bilirubin, markers of iron status, and the development of coronary artery disease (CAD). RESEARCH DESIGN AND METHODS: We screened the allelic frequencies of (GT)(n) repeats in the HO-1 gene promoter in 986 unrelated individuals who underwent coronary angiography. Serum bilirubin and markers of iron status were evaluated. RESULTS: The distribution of numbers of (GT)(n) repeats was divided into two subclasses: class S included shorter (<27) repeats, and class L included longer (>or=27) repeats. Among those with diabetes, subjects with the L/L genotype had significantly lower bilirubin levels than those with S/S and S/L genotypes (0.70 +/- 0.22 vs. 0.81 +/- 0.24 mg/dl, P = 0.001) and higher serum ferritin values (4.76 +/- 0.72 vs. 4.28 +/- 1.05 mug/l for log ferritin, P = 0.001). Compared with those carrying the S allele, diabetic subjects with the L/L genotype had an almost threefold increase in CAD risk after controlling for conventional risk factors (odds ratio 2.81, [95% CI 1.22-6.47], P = 0.015). With adjustment for both serum bilirubin and ferritin, the effect of HO-1 promoter polymorphism on susceptibility to CAD disappeared. CONCLUSIONS: Length polymorphism in the HO-1 gene promoter is correlated with susceptibility to CAD in diabetic patients, and this effect might be conveyed through its influence on serum bilirubin and ferritin.