Download PDF
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   *
1   Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria
,
Markus Exner   *
1   Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria
,
Martin Schillinger
2   Department of Internal Medicine II, Division of Angiology, University of Vienna, Medical School, Vienna, Austria
,
Rodrig Marculescu
1   Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria
,
Raute Sunder-Plassmann
1   Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria
,
Marianne Raith
1   Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria
,
Nelli Jordanova
3   Department of Internal Medicine II, Division of Cardiology, University of Vienna, Medical School, Vienna, Austria
,
Johann Wojta
3   Department of Internal Medicine II, Division of Cardiology, University of Vienna, Medical School, Vienna, Austria
,
Christine Mannhalter
1   Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria
,
Oswald F. Wagner
1   Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria
,
Kurt Huber
4   3rd Medical Department for Cardiology and Emergency Medicine, Wilhelminenspital, Vienna, Austria
› Author AffiliationsFinancial support: This work was supported by grant #15231 of the Austrian “Fonds zur Förderung der wissenschaftlichen Forschung”
Further Information

Publication History

Received 15 May 2003

Accepted after revision 08 September 2003

Publication Date:
30 November 2017 (online)

    Permissions and Reprints

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

* Georg Endler and Markus Exner contributed equally to the present paper.


 

  • 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.
    CrossrefPubMedGoogle Scholar
  • 2 Maines MD. Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. Faseb J 1988; 02 (10) 2557-68.
    CrossrefPubMedGoogle Scholar
  • 3 Tenhunen R, Marver HS, Schmid R. Microsomal heme oxygenase. Characterization of the enzyme. J Biol Chem 1969; 244 (23) 6388-94.
    PubMedGoogle Scholar
  • 4 Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol 1997; 37: 517-54.
    CrossrefPubMedGoogle Scholar
  • 5 Marks GS, Brien JF, Nakatsu K, McLaughlin BE. Does carbon monoxide have a physiological function?. Trends Pharmacol Sci 1991; 12 (05) 185-8.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 32 Mayer M. Association of serum bilirubin concentration with risk of coronary artery disease. Clin Chem 2000; 46 (11) 1723-7.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 35 Barter P. Effects of inflammation on highdensity lipoproteins. Arterioscler Thromb Vasc Biol 2002; 22 (07) 1062-3.
    CrossrefPubMedGoogle Scholar