Angiotensin II type 1 receptor gene polymorphism is associated with the severity but not prevalence of coronary artery disease

To the Editor: Angiotensin II, produced by the angiotensin-I-converting enzyme and other proteases, is a potent mediator of vasoconstriction and endothelial proliferation. At the same time, it augments peripheral sympathetic transmission and adrenal release of epinephrine (1). It is assumed to be strongly involved in cardiovascular diseases. Major biological effects are mediated by the angiotensin II type 1 receptor (AT1R). In heart failure, AT1R-mRNA downregulation has been described (2). Further, a polymorphism in the 3% untranslated region of the AT1R gene, which corresponds to an adenine cytosine transversion at nucleotide position 1166 of the mRNA sequence, is associated with essential hypertension in Caucasians (3, 4). However, conflicting results have been reported (5–7). There are also equivocal findings for development of coronary artery disease (CAD) and myocardial infarction in relation to AT1R genotypes (8–11). A positive correlation was found in some subgroups of patients and in 6itro findings in human mammarian arteries showed a greater contractile response to phenylephrine in the CC genotype (12). To investigate the contribution of the A/C polymorphism at nucleotide position 1166 of the AT1R gene in our population, 818 consecutive patients who underwent coronary angiography in our institution were genotyped. Genomic DNA was extracted from blood leukocytes and AT1R genotypes were determined by PCR as previously described (13). Individuals with cardiomyopathy, significant valvular disease, history of coronary bypass or percutaneous transluminal angioplasty, significant (]50%) left main stem disease, failure of DNA extraction or with any missing data were excluded from the analysis. The final cohort consisted of 587 patients (150 female, 437 male). A ]50% stenosis of a great coronary vessel in the coronary angiogram was considered for the diagnosis of CAD. Our group was thus divided into 361 CAD patients and 226 patients without significant CAD, serving as controls. Various angiographic scores were calculated to quantify coronary arteriosclerosis (10). Each coronary segment was graded from 0 to 3 (Lumen narrowing 525%=grade 0, 550%=grade 1, 575%= grade 2 and \75%=grade 3). Three different scores were calculated: 1) coronary score (range 0–3) representing the number of coronary arteries with at least one stenosis \75%, often accompanied with clinical significant stenosis; 2) severity score (range 1–3) was calculated by the average grade of coronary segments with stenosis \25%. This score characterises the severity of stenosis in affected vessels; 3) arteriosclerosis score (range 0– 3) was computed as the mean grade of all 11 analysed coronary segments and describes the overall degree of coronary arteriosclerosis. As presented in Table 1, there was no difference in the frequency of the A and C allele in CAD as compared to controls. The observed values fulfilled the Hardy–Weinberg equilibrium. The A/C ratio was similar to other Caucasian populations (8, 10, 11, 13, 14). In logistic regression analysis established risk factors (age, male sex, smoking, LDLcholesterol levels and diabetes) correlated with CAD but AT1R genotype did not. Angiographic scores were calculated in all CAD patients. The CC genotype was associated with a significantly increased severity score (Table 1). Trends in arteriosclerotic and coronary scores were not statistically significant. In multiple regression analysis – including conventional risk factors and AT1R gene polymorphism – the presence of the C allele and smoking were detected as independent risk factors for severity of CAD. Our study population consisted of individuals having undergone coronary angiography, therefore our control group might have been influenced by a