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

Abstract

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.—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)

Vitamin D receptor gene polymorphisms in type 1 diabetes mellitus: a new pattern from Khorasan province, Islamic Republic of Iran

“…It seems that vitamin D functions may play a role in the pathogenesis of hypertension as a negative endocrine regulator of renin biosynthesis [27] and have a favourable effect on cardiovascular disease [28,29]. Other researchers have also reported an association between the bb genotype and severe coronary stenosis [30].…”

Vitamin D receptor gene polymorphisms are associated with obesity in type 2 diabetic subjects with early age of onset

“…These included variations in circulating levels of 1,25-(OH) 2 D 3 (10), variations in bone mineral density (11), modulation of intrauterine and early postnatal growth (12), severity of coronary artery disease (13), and also susceptibility to type 1 diabetes (14,15) and variations in insulin secretion in response to glucose (16). Indeed, an association of alleles of single nucleotide polymorphisms (SNPs) in the VDR gene with increased or decreased insulin secretion in response to an oral glucose tolerance test was observed in a cohort of Bangladeshi Asians (16) recruited from a population considered at risk for type 2 diabetes (5).…”

Genetic Instability, DNA Damage and Atherosclerosis

“…Several studies have demonstrated the presence of DNA-adducts in abdominal aorta fragments taken at surgery from patients suffering of severe atherosclerotic lesions. 15,[33][34][35] DNA-adduct levels were significantly correlated with the occurrence of atherogenic risk factors and the severity of coronary artery disease. 15,33 The presence of chromosomal alterations and oxidative DNA damage has been recently demonstrated by our group by using the micronucleus test (MN) and the comet assay which are sensitive biomarkers of genetic damage.…”

“…15,[33][34][35] DNA-adduct levels were significantly correlated with the occurrence of atherogenic risk factors and the severity of coronary artery disease. 15,33 The presence of chromosomal alterations and oxidative DNA damage has been recently demonstrated by our group by using the micronucleus test (MN) and the comet assay which are sensitive biomarkers of genetic damage. [36][37][38][39] Our data indicated an overall elevation of chromosomal alteration and oxidative DNA damage in peripheral blood lymphocytes of patients with coronary artery disease.…”