Background: The renin-angiotensin-aldosterone system (RAAS) plays a significant role in the development of hypertensive cardiac and vascular remodeling. Recently, several genetic variants of its key components, which may be clinically relevant and thus prove to be useful in the evaluation of cardiovascular risk, have been described. We therefore investigated the association between ACE I/D, AGT M235T, and AT1 A1266C gene polymorphisms and early signs of target organ damage in 215 untreated patients with essential hypertension (EH).
Methods: Genotyping was based on the polymerase chain reaction technique, with further restriction analysis when required. Albuminuria was measured as the albumin-to-creatinine ratio (ACR). The left ventricular mass index (LVMI) was assessed by echocardiography (LVH = LVMI > or = 125 g/m2), carotid wall thickness (IMT) by an ultrasonographic (US) scan, and retinal vascular changes by direct ophthalmoscopy (Keith-Wagener classification).
Results: The prevalence of microalbuminuria (Mi), LVH, and retinal vascular changes was 14, 46, and 74%, respectively. ACE, AGT, and AT1 genotype distribution was in agreement with the Hardy-Weinberg equilibrium. There was no difference in age, duration of disease, body mass index (BMI), blood pressure, and lipid profile when data were analyzed on the basis of genotype. Serum levels of angiotensin-converting enzyme (ACE) were related to the ACE genotype (10.2 +/- 0.5, DD; 8.2 +/- 0.3, ID; 6.5 +/- 0.4 IU/mL, II; P < 0. 0001 by analysis of variance). The ACE genotype independently influences serum ACE levels and accounts for approximately 14% of its variations (F = 26.7, r2 = 0.1393, df 1 to 214, P < 0.0001). Patients with DD and ID genotypes showed higher levels of ACR (1.59 +/- 0.2, DD + ID; 0.8 +/- 0.2 mg/mmol, II; P < 0.006 by ANOVA) and bigger LVMI (124.1 +/- 2.3, DD + ID vs. 117.8 +/- 3.6 g/m2, II; P < 0.01 by ANOVA). No differences in the prevalence and degree of target organ damage (TOD) were found when data were analyzed on the basis of the AGT and AT1 genotypes, respectively. Potentially unfavorable combinations of genotypes were also investigated by K-means cluster analysis. Two subgroups of patients were identified (cluster 1, N = 70; cluster 2, N = 57), and each differed significantly with regards to the presence and degree of TOD and patterns of RAAS gene polymorphisms (F, 15.97 for ACR; F, 7.19 for IMT; F, 217.03 for LVMI; F, 3.91 for ACE; F, 4.06 for AGT; and F, 5. 22 for AT1; df 1 to 214, P < 0.02, for each one of the variables examined).
Conclusion: The D allele of the ACE gene may be an independent risk factor for the development of target organ damage, and evaluating it could be useful for assessing cardiovascular risk in EH. Unfavorable patterns of RAAS genotypes seem to predispose patients to subclinical cardiovascular disease in EH.