Molecular basis of salt sensitivity in human hypertension - Evaluation of renin-angiotensin-aldosterone system gene polymorphisms

We analyzed the association between salt sensitivity in essential hypertens ion and 8 genetic polymorphisms in 6 genes of the renin-angiotensin aldoste rone system. Seventy-one patients with essential hypertension were classifi ed as salt sensitive or salt resistant by means of the 24-hour ambulatory b lood pressure (BP) change to high salt intake. The polymorphisms evaluated correspond to the following genes: ACE (I/D), angiotensinogen (M235T), angi otensin II type 1 receptor (A1166C), 11 beta -Hydroxysteroid dehydrogenase type 2 (11 beta HSD2) (G534A), aldosterone synthase (C-344T and Intron 2 co nversion), and the mineralocorticoid receptor (G3514C and A4582C); all were determined using standard polymerase chain reaction methods. Thirty-five p atients (49%) were classified as salt sensitive. We analyzed the BP respons e to high salt intake among genotypes and found a significant association f or ACE I/D and 11 beta HSD2 G534A polymorphisms. Patients homozygous for th e insertion allele of the ACE gene (II) had a significantly higher BP incre ase with high salt intake than did patients homozygous for the deletion all ele (DID). Heterozygous patients (ID) exhibited an intermediate response. T he prevalence of salt-sensitive hypertension was also significantly higher (P=0.003) in II (68%) and DI patients (59%) compared with DD hypertensives (19%). With respect to 11 beta HSD2 G534A, patients with the GG genotype ha d a significantly higher systolic BP increase with high salt intake than di d GA patients. In addition, plasma renin activity suppression in response t o high salt was significantly greater in GA patients than in GG patients. T he prevalence of salt-sensitive hypertension was 14.3% in GA patients and 5 0.8% in GG patients (P=0.067). In conclusion, the I allele of ACE I/D polym orphism is significantly associated to salt-sensitive hypertension. The BP response to high salt intake was different among genotypes of ACE I/D and 1 1 beta HSD G534A, suggesting that these polymorphisms may be potentially us eful genetic markers of salt sensitivity.