Putative susceptibility markers of coronary artery disease: association between VDR genotype, smoking, and aromatic DNA adduct levels in human right atrial tissue.
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 (rs=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.
Department of Health Risk Analysis and Toxicology, Maastricht University, 6200 MD Maastricht, The Netherlands. f.vanschooten@grat.unimaas.nl
F J
FJ
Van Schooten
A
A
Hirvonen
L M
LM
Maas
B A
BA
De Mol
J C
JC
Kleinjans
D A
DA
Bell
J D
JD
Durrer
D000328:Adult; D000368:Aged; D015415:Biomarkers; D002117:Calcitriol / Q000097:blood; D017023:Coronary Angiography; D003327:Coronary Disease / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006325:Heart Atria; D006331:Heart Diseases / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006937:Hypercholesterolemia / Q000453:epidemiology; D006973:Hypertension / Q000453:epidemiology; D008658:Inactivation, Metabolic / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000737:chemistry*; D011084:Polycyclic Aromatic Hydrocarbons / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics; D011110:Polymorphism, Genetic; D018167:Receptors, Calcitriol / Q000235:genetics*; D012307:Risk Factors; D012906:Smoke / Q000032:analysis; D012907:Smoking / Q000009:adverse effects* / Q000453:epidemiology / Q000235:genetics; D016540:Smoking Cessation; D014807:Vitamin D / Q000502:physiology
D015415:Biomarkers; D018736:DNA Adducts; D007527:Isoenzymes; D011084:Polycyclic Aromatic Hydrocarbons; D018167:Receptors, Calcitriol; D012906:Smoke; D014807:Vitamin D; D005982:Glutathione Transferase; D002117:Calcitriol