Atr Gene Polymorphism And Atherosclerosisrelated Diseases

Coronary artery disease (CAD) is a major public health problem in industrialized countries. Dyslipidemia, arterial hypertension, and diabetes mellitus, the main risk factors for CAD apart tobacco consumption, are influenced by both environmental and genetic factors. Several studies have suggested that the activation of the RAS could be an important contributor to CAD. The best-documented of associations between the occurrence of CAD and polymorphisms in genes RAS component is the I/D polymorphism of the ACE gene. After the initial work of Cambien et al. (67), who first suggested the potential role of the ACE D allele as an independent risk factor for myocardial infarction (MI), other case-control studies either confirmed or were in disagreement with their findings (68-70). The M235T variant of AG gene has also been associated with MI but, as in hypertension, with ethnic variability (19). A1166C polymorphism in AT1R gene does not seem to be a direct risk factor for CAD or MI, but, in many studies, it has been observed to have synergistic effects with ACE I/D polymorphism (53,71-73); in particular the highest risks were shown for patients with both ACE DD and AT1R CC genotypes. Conversely to the former studies, other examinations did not find an association between A1116C polymorphism in AT1R gene and CAD or MI, as well as no interaction between this polymorphism and I/D polymorphism in ACE gene (74-76) or independently of BP (77). Moreover, Olivieri et al. (78) did not find associations between AG M235T or AT1R A1116C polymorphism and atheromatous renal artery stenosis, whereas their results suggested a predisposing role for ACE D allele in the development and progression of this atherosclerosis related disease. AT1R A1116C polymorphism was also not related to hypercholesterolemia, in particular in subjects with essential hypertension (79); but in another study C allele was overrepresented in familial hypercholesterolemia with CAD (80). An association was found between AT1R C allele and ACE D allele in patients with CAD and malignant ventricular arrhythmia treated with an implantable cardioverter defibrillator (81). Recently, Gruchala et al. (82), evaluating left ventricular size and performance of patients with angiographically confirmed CAD by echocardio-graphy, did not find relationships between AT1R A1116C polymorphism and left ventricular parameters. In two studies, patients carrying the AT1R CC genotype have greater vasoconstriction in coronary vessels, as well as in response to Ang II infusion (83), than after intravenous injection of methylergonovine maleate, a potent vasoconstrictor whose effects have been explored in CAD (84); but Steeds et al. (85) did not find differences in vasomotor function in isolated human mesenteric resistance arterioles, but an increase in sensitivity to prostaglandin F2a in arterioles from patients with C allele in ATjR gene. Vuagnat et al. (86) found the same following Ang II infusion to assess familial resemblance in hypertensive patients. Ortlepp et al. (87) concluded that left ventricular hypertrophy in patients with aortic stenosis was not determined by five genetic polymorphisms in RAS, particularly in ACE, ATjR, and AG genes. In a large population-based cohort of older adults, Hindorff et al. (88) did not observe any association of this ATjR gene polymorphism with incident cardiovascular events. Thus, taken alone, the A1166C polymorphism in ATjR gene neither represents a risk factor for adverse events complicating coronary interventions nor seems to have significant impact on further long-term processes such as development and severity of CAD (89-91). Recently, polymorphisms in AT2R gene were explored as predictors of CAD. Ye et al. (73) did not find any association between +1291 G/T or +1297 G/A polymorphism and coronary extent scores defined essentially by the number of coronary segments with significative stenosis. On the other hand, Jones et al. (77) demonstrated that hypertensive carriers with AT2R 1675A/3123A haplotype were at most risk for a cardiovascular event.

In conclusion, among these three well-documented polymorphisms in RAS, i.e., I/D polymorphism in the ACE gene, M235T variant of AG, and A1166C SNP in ATjR gene, only two types of relationships seem to be confirmed: (1) D allele of the ACE gene as risk factor for CAD and MI; and (2) C allele of A1166C in the ATjR gene, when associated with ACE D allele, as contributor to susceptibility of CAD and to interindividual differences in severity of cardiovascular disease.

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