Putative susceptibility markers of coronary artery disease: association between VDR genotype, smoking, and aromatic DNA adduct levels in human right atrial tissue

^a Department of Health Risk Analysis and Toxicology, Maastricht University, 6200 MD Maastricht, The Netherlands
^b Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland
^c Department of Cardiothoracic Surgery
^d Department of Cardiology, Academical Medical Center, University of Amsterdam, Amsterdam, The Netherlands
^e Laboratory of Biochemical Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Cancer and cardiovascular diseases share risk factors such as smoking, and the onset of both diseases have been suggested to have a common mechanistic basis. The binding of carcinogens to DNA (carcinogen-DNA adducts), genetic polymorphisms in carcinogen-detoxifying enzymes glutathione S-transferases (GSTs), and genetic polymorphisms in the vitamin D receptor (VDR) are among the candidates for modifiers of cancer risk. We determined whether these biomarkers could be related to individual characteristics of patients suffering from cardiovascular diseases. For that purpose, DNA from the right atrial appendage of 41 patients who underwent open heart surgery was analyzed for smoking-related DNA adducts and polymorphisms in GSTM1, GSTT1, and VDR genes. Statistical analysis was used to identify any patient's characteristics associated with these molecular markers. Our results showed that heart tissue of cigarette smokers contained a variety of aromatic DNA adducts in significantly elevated levels compared to ex-smokers (P<0.01) or nonsmokers (P<0.001). A linear relationship was observed between DNA adduct levels and daily cigarette smoking (r_s=0.73; P=0.0003). Since cardiac myocytes are terminally differentiated cells that have lost their ability to divide and seemingly have limited DNA repair capacities, their levels might accumulate with time and thereby affect heart cell function or viability. Substantial interindividual differences between DNA adduct levels were observed, and persons with severe coronary artery disease (CAD), as assessed by coronary angiography, had higher DNA adduct levels than persons with no or mild CAD (P=0.04). As polymorphisms in GST genes have been shown to modulate DNA adduct levels and risk for lung cancer in smokers, we explored for the first time whether the GST polymorphisms could also explain deviating heart DNA adduct levels and CAD risk. However, no relation could be found between these covariants. In contrast, a VDR genotype, which has been associated with decreased serum levels of the active hormonal form of vitamin D and increased risk for certain cancers, seemed to be related to severity of CAD (P=0.025). Our findings support the hypothesis that smoking-related DNA damage may be involved in the onset of cardiovascular diseases and suggest that VDR genotype may be a useful susceptibility marker of CAD.—van Schooten, F. J., Hirvonen, A., Maas, L. M., de Mol, B. A., Kleinjans, J. C. S., Bell, D. A., Durrer, J. D. Putative susceptibility markers of coronary artery disease: association between VDR genotype, smoking, and aromatic DNA adduct levels in human right atrial tissue. FASEB J. 12, 1409–1417 (1998)

Key Words: smoking-related DNA adducts • genetic polymorphisms • CAD

This article has been cited by other articles:

				P. Vineis Smoking and impact on health Eur. Respir. Rev., December 1, 2008; 17(110): 182 - 186. [Abstract] [Full Text] [PDF]

				E. Taioli Gene-environment interaction in tobacco-related cancers Carcinogenesis, August 1, 2008; 29(8): 1467 - 1474. [Abstract] [Full Text] [PDF]

				J. Zhao, R. Harper, A. Barchowsky, and Y. P. P. Di Identification of multiple MAPK-mediated transcription factors regulated by tobacco smoke in airway epithelial cells Am J Physiol Lung Cell Mol Physiol, August 1, 2007; 293(2): L480 - L490. [Abstract] [Full Text] [PDF]

				D. M.v. Leeuwen, E. v. Agen, R. W.H. Gottschalk, R. Vlietinck, M. Gielen, M. H.M.v. Herwijnen, L. M. Maas, J. C.S. Kleinjans, and J. H.M.v. Delft Cigarette smoke-induced differential gene expression in blood cells from monozygotic twin pairs Carcinogenesis, March 1, 2007; 28(3): 691 - 697. [Abstract] [Full Text] [PDF]

				D. M. van Leeuwen, R. W. H. Gottschalk, M. H. van Herwijnen, E. J. Moonen, J. C. S. Kleinjans, and J. H. M. van Delft Differential Gene Expression in Human Peripheral Blood Mononuclear Cells Induced by Cigarette Smoke and Its Constituents Toxicol. Sci., July 1, 2005; 86(1): 200 - 210. [Abstract] [Full Text] [PDF]

				P.E. Norman and J.T. Powell Vitamin D, Shedding Light on the Development of Disease in Peripheral Arteries Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 39 - 46. [Abstract] [Full Text] [PDF]

				M C Cornelis, A El-Sohemy, and H Campos Genetic polymorphism of CYP1A2 increases the risk of myocardial infarction J. Med. Genet., October 1, 2004; 41(10): 758 - 762. [Abstract] [Full Text] [PDF]

				P.M. Timms, N. Mannan, G.A. Hitman, K. Noonan, P.G. Mills, D. Syndercombe-court, E. Aganna, C.P. Price, and B.J. Boucher Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM, December 1, 2002; 95(12): 787 - 796. [Abstract] [Full Text] [PDF]

				D. H. Phillips Smoking-related DNA and protein adducts in human tissues Carcinogenesis, December 1, 2002; 23(12): 1979 - 2004. [Abstract] [Full Text] [PDF]

				M. G. Andreassi, N. Botto, A. Rizza, M. G. Colombo, C. Palmieri, S. Berti, S. Manfredi, S. Masetti, A. Clerico, and A. Biagini Deoxyribonucleic acid damage in human lymphocytes after percutaneous transluminal coronary angioplasty J. Am. Coll. Cardiol., September 4, 2002; 40(5): 862 - 868. [Abstract] [Full Text] [PDF]

				B.-W. Ogunkolade, B. J. Boucher, J. M. Prahl, S. A. Bustin, J. M. Burrin, K. Noonan, B. V. North, N. Mannan, M. F. McDermott, H. F. DeLuca, et al. Vitamin D Receptor (VDR) mRNA and VDR Protein Levels in Relation to Vitamin D Status, Insulin Secretory Capacity, and VDR Genotype in Bangladeshi Asians Diabetes, July 1, 2002; 51(7): 2294 - 2300. [Abstract] [Full Text] [PDF]

				Y.-p. Sun, B.-q. Zhu, A. E. Browne, R. E. Sievers, J. M. Bekker, K. Chatterjee, W. W. Parmley, and S. A. Glantz Nicotine Does Not Influence Arterial Lipid Deposits in Rabbits Exposed to Second-Hand Smoke Circulation, August 14, 2001; 104(7): 810 - 814. [Abstract] [Full Text] [PDF]

				A. IZZOTTI, C. CARTIGLIA, J. LEWTAS, and S. DE FLORA Increased DNA alterations in atherosclerotic lesions of individuals lacking the GSTM1 genotype FASEB J, March 1, 2001; 15(3): 752 - 757. [Abstract] [Full Text] [PDF]

				M. H. WILSON, P. J. GRANT, L. J. HARDIE, and C. P. WILD Glutathione S-transferase M1 null genotype is associated with a decreased risk of myocardial infarction FASEB J, April 1, 2000; 14(5): 791 - 796. [Abstract] [Full Text]