Genetic polymorphism of the renin-angiotensin system and organ damage in essential hypertension

Background. The renin-angiotensin-aldosterone system (RAAS) plays a signifi cant role in the development of hypertensive cardiac and vascular remodelin g. Recently, several genetic variants of its key components, which may be c linically relevant and thus prove to be useful in the evaluation of cardiov ascular risk, have been described. We therefore investigated the associatio n between ACE I/D, AGT M235T, and AT(1) A1266C gene polymorphisms and early signs of target organ damage in 215 untreated patients with essential hype rtension (EH). Methods. Genotyping was based on the polymerase chain reaction technique, w ith further restriction analysis when required. Albuminuria was measured as the albumin-to-creatinine ratio (ACR). The left ventricular mass index (LV MI) was assessed by echocardiography (LVH = LVMI greater than or equal to 1 25 g/m(2)), carotid wall thickness (IMT) by an ultrasonographic (US) scan, and retinal vascular changes by direct ophthalmoscopy (Keith-Wagener classi fication). Results. The prevalence of microalbuminuria (Mi), LVH, and retinal vascular changes was 14, 46, and 74%, respectively. ACE, AGT, and AT1 genotype dist ribution was in agreement with the Hardy-Weinberg equilibrium. There was no difference in age, duration of disease, body mass index (BMI), blood press ure, and lipid profile when data were analyzed on the basis of genotype. Se rum levels of angiotensin-converting enzyme (ACE) were related to the ACE g enotype (10.2 +/- 0.5, DD; 8.2 +/- 0.3, ID; 6.5 +/- 0.4 IU/mL, II; P < 0.00 01 by analysis of variance). The ACE genotype independently influences seru m ACE levels and accounts for approximately 14% of its variations (F = 26.7 , r(2) = 0.1393, df 1 to 214, P < 0.0001). Patients with DD and ID genotype s 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 d egree of target organ damage (TOD) were found when data were analyzed on th e basis of the AGT and AT1 genotypes, respectively. Potentially unfavorable combinations of genotypes were also investigated by K-means cluster analys is. 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 AT(1); df 1 to 214, P < 0.02, for each one of the variables exam ined). 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 usef ul for assessing cardiovascular risk in EH. Unfavorable patterns of RAAS ge notypes seem to predispose patients to subclinical cardiovascular disease i n EH.