Combination of renin-angiotensin system polymorphisms is associated with altered renal sodium handling and hypertension

Genes of the renin-angiotensin-aldosterone system (RAAS) are natural candidates for sodium homeostasis and blood pressure regulation. To investigate the effect of a combination of polymorphisms of RAAS genes on renal sodium handling and blood pressure, 918 participants to the Olivetti Heart Study were genotyped for the following polymorphisms: I/D of angiotensin converting enzyme (ACE), M235T of angiotensinogen (AGT), A1166C of angiotensin II type-1 receptor (AT1R), and C-344T of aldosterone synthase (CYP11B2). The segmental renal sodium handling was evaluated by the fractional excretions of exogenous lithium (FE-Li), uric acid (FE-UA), and sodium (FE-Na). Twenty-eight carriers of triple homozygosity for M ( AGT), A ( AT1R), and C ( CYP11B2) in the presence of the D allele of ACE (DD/ID) showed lower FE-Li (20.0% +/- 5.9% versus 25.0% +/- 7.5%; P = 0.004; mean +/- SD), FE-UA (6.3% +/- 2.0% versus 8.2% +/- 2.7%; P = 0.001), and FE-Na ( 0.96% +/- 0.41% versus 1.22% +/- 0.61%; P = 0.004) as compared with all other allelic combinations ( n = 890), independently from age and body mass, suggesting an enhanced rate of proximal tubular sodium reabsorption. The carriers of the MM, AA, CC, DD/ ID combination showed a substantially higher probability of being hypertensive (OR: 3.4 [(99% CI: 1.1 to 10.1]), independently of age and body mass. This relatively rare combination of allelic variants of candidate genes of the RAAS is associated with a significant alteration in proximal renal sodium handling and with higher risk of hypertension, suggesting that a combination of polymorphic variants at different candidate loci may affect phenotypic expression even in the absence of detectable effects of each variant at any single locus.