A microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with increased bilirubin and HDL levels but not with coronary artery disease

Georg Endler; Markus Exner; Martin Schillinger; Rodrig Marculescu; Raute Sunder-Plassmann; Marianne Raith; Nelli Jordanova; Johann Wojta; Christine Mannhalter; Oswald F. Wagner; Kurt Huber

doi:10.1160/TH03-05-0291

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 91(01): 155-161
DOI: 10.1160/TH03-05-0291

Cell Signalling and Vessel Remodelling

Schattauer GmbH

A microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with increased bilirubin and HDL levels but not with coronary artery disease

Georg Endler^*

¹Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria

,

Markus Exner^*

¹Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria

,

Martin Schillinger

²Department of Internal Medicine II, Division of Angiology, University of Vienna, Medical School, Vienna, Austria

,

Rodrig Marculescu

¹Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria

,

Raute Sunder-Plassmann

¹Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria

,

Marianne Raith

¹Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria

,

Nelli Jordanova

³Department of Internal Medicine II, Division of Cardiology, University of Vienna, Medical School, Vienna, Austria

,

Johann Wojta

³Department of Internal Medicine II, Division of Cardiology, University of Vienna, Medical School, Vienna, Austria

,

Christine Mannhalter

¹Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria

,

Oswald F. Wagner

¹Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria

,

Kurt Huber

⁴3rd Medical Department for Cardiology and Emergency Medicine, Wilhelminenspital, Vienna, Austria

› Author Affiliations

Abstract

Summary

Heme oxygenase 1 (HO-1) is involved in the generation of the endogenous anti-oxidant bilirubin which exerts beneficial effects against arteriosclerosis. A (GT) repeat polymorphism in the HO-1 promoter region modulates HO-1 expression in response to oxidative stress. Recently, this polymorphism has been reported to protect from coronary artery disease in Orientals. We intended to confirm this observation in Caucasians.

We studied 649 individuals with myocardial infarction (n=258), stable coronary artery disease (n=180) and controls without coronary artery disease (n=211). Carriers of short alleles (<25 repeats) had higher bilirubin levels (median 0.66 mg/dL, IQR 0.49 to 0.91) compared to non-carriers (median 0.61mg/dL, IQR 0.45 to 0.82; p=0.03) and a more favourable lipid profile (HDL median 47mg/dL, IQR 40 to 50 vs. median 45, IQR 37 to 55, p=0.01; triglycerides median 118mg/dL, IQR 87 to 174 vs. median 132, IQR 97 to 191, p=0.03). However, no significant differences of the genotype distribution were observed between the three groups in this Caucasian study population (p=0.94).

Although potentially beneficial effects of the short HO-1 allele on lipid profile and serum bilirubin were observed, in contrast to Orientals, the HO-1 genotype was not associated with coronary artery disease in Caucasians.

Keywords

Heme oxygenase 1 - promoter polymorphism - coronary artery disease - bilirubin - Caucasians

Full Text

References

References
1 Siow RC, Sato H, Mann GE. Heme oxygenase-carbon monoxide signalling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide?. Cardiovasc Res 1999; 41 (02) 385-94.
2 Maines MD. Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. Faseb J 1988; 02 (10) 2557-68.
3 Tenhunen R, Marver HS, Schmid R. Microsomal heme oxygenase. Characterization of the enzyme. J Biol Chem 1969; 244 (23) 6388-94.
4 Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol 1997; 37: 517-54.
5 Marks GS, Brien JF, Nakatsu K, McLaughlin BE. Does carbon monoxide have a physiological function?. Trends Pharmacol Sci 1991; 12 (05) 185-8.
6 Schmidt HH, Lohmann SM, Walter U. The nitric oxide and cGMP signal transduction system: regulation and mechanism of action. Biochim Biophys Acta 1993; 1178 (02) 153-75.
7 Yamaguchi T, Horio F, Hashizume T. et al. Bilirubin is oxidized in rats treated with endotoxin and acts as a physiological antioxidant synergistically with ascorbic acid in vivo. Biochem Biophys Res Commun 1995; 214 (01) 11-9.
8 Neuzil J, Stocker R. Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation. J Biol Chem 1994; 269 (24) 16712-9.
9 Amit Y, Boneh A. Bilirubin inhibits protein kinase C activity and protein kinase C-mediated phosphorylation of endogenous substrates in human skin fibroblasts. Clin Chim Acta 1993; 223 (1-2): 103-11.
10 Mietus-Snyder M, Friera A, Glass CK. et al. Regulation of scavenger receptor expression in smooth muscle cells by protein kinase C: a role for oxidative stress. Arterioscler Thromb Vasc Biol 1997; 17 (05) 969-78.
11 Wang LJ, Lee TS, Lee FY. et al. Expression of heme oxygenase-1 in atherosclerotic lesions. Am J Pathol 1998; 152 (03) 711-20.
12 Siow RC, Ishii T, Sato H. et al. Induction of the antioxidant stress proteins heme oxygenase-1 and MSP23 by stress agents and oxidised LDL in cultured vascular smooth muscle cells. FEBS Lett 1995; 368 (02) 239-42.
13 Ishikawa K, Navab M, Leitinger N. et al. Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL. J Clin Invest 1997; 100 (05) 1209-16.
14 Yamada N, Yamaya M, Okinaga S. et al. Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema. Am J Hum Genet 2000; 66 (01) 187-95.
15 Schillinger M, Exner M, Mlekusch W. et al. Heme oxygenase-1 gene promoter polymorphism is associated with abdominal aortic aneurysm. Thromb Res 2002; 106 (02) 131.
16 Exner M, Schillinger M, Minar E. et al. Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with restenosis after percutaneous transluminal angioplasty. J Endovasc Ther 2001; 08 (05) 433-40.
17 Schillinger M, Exner M, Mlekusch W. et al. Heme Oxygenase-1 Genotype Is a Vascular Anti-inflammatory Factor Following Balloon Angioplasty. J Endovasc Ther 2002; 09 (04) 385-94.
18 Chen YH, Lin SJ, Lin MW. et al. Micro-satellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients. Hum Genet 2002; 111 (01) 1-8.
19 Kaneda H, Ohno M, Taguchi J. et al. Heme oxygenase-1 gene promoter polymorphism is associated with coronary artery disease in Japanese patients with coronary risk factors. Arterioscler Thromb Vasc Biol 2002; 22 (10) 1680-5.
20 Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. Eur Heart J 2000; 21 (18) 1502-13.
21 Watanabe T, Akutsu Y, Yamanaka H. et al. Exercise-induced ST-segment depression: imbalance between myocardial oxygen demand and myocardial blood flow. Acta Cardiol 2000; 55 (01) 25-31.
22 Harris TJ, Cook DG, Wicks PD. et al. Impact of the new American Diabetes Association and World Health Organisation diagnostic criteria for diabetes on subjects from three ethnic groups living in the UK. Nutr Metab Cardiovasc Dis 2000; 10 (06) 305-9.
23 Morita T, Perrella MA, Lee ME. et al. Smooth muscle cell-derived carbon monoxide is a regulator of vascular cGMP. Proc Natl Acad Sci U S A 1995; 92 (05) 1475-9.
24 Amersi F, Buelow R, Kato H. et al. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest 1999; 104 (11) 1631-9.
25 Motterlini R, Gonzales A, Foresti R. et al. Heme oxygenase-1-derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo. Circ Res 1998; 83 (05) 568-77.
26 Terry CM, Clikeman JA, Hoidal JR. et al. Effect of tumor necrosis factor-alpha and interleukin-1 alpha on heme oxygenase-1 expression in human endothelial cells. Am J Physiol 1998; 274 (3 Pt 2): H883-91.
27 Hancock WW, Gao W, Shemmeri N. et al. Immunopathogenesis of accelerated allograft rejection in sensitized recipients: humoral and nonhumoral mechanisms. Transplantation 2002; 73 (09) 1392-7.
28 Yachie A, Niida Y, Wada T. et al. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 1999; 103 (01) 129-35.
29 Ishikawa K, Sugawara D, Goto J. et al. Heme oxygenase-1 inhibits atherogenesis in Watanabe heritable hyperlipidemic rabbits. Circulation 2001; 104 (15) 1831-6.
30 Ishikawa K, Sugawara D, Wang X. et al. Heme oxygenase-1 inhibits atherosclerotic lesion formation in ldl-receptor knockout mice. Circ Res 2001; 88 (05) 506-12.
31 Kaneda H, Ohno M, Taguchi J. et al. Heme oxygenase-1 gene promoter polymorphism is associated with coronary artery disease in Japanese patients with coronary risk factors. Arterioscler Thromb Vasc Biol 2002; 22 (10) 1680-5.
32 Mayer M. Association of serum bilirubin concentration with risk of coronary artery disease. Clin Chem 2000; 46 (11) 1723-7.
33 Schwertner HA, Jackson WG, Tolan G. Association of low serum concentration of bilirubin with increased risk of coronary artery disease. Clin Chem 1994; 40 (01) 18-23.
34 Djousse L, Levy D, Cupples LA. et al. Total serum bilirubin and risk of cardiovascular disease in the Framingham offspring study. Am J Cardiol 2001; 87 (10) 1196-200 A4, 7.
35 Barter P. Effects of inflammation on highdensity lipoproteins. Arterioscler Thromb Vasc Biol 2002; 22 (07) 1062-3.