Combination of Renin-Angiotensin System Polymorphisms Is Associated with Altered Renal Sodium Handling and Hypertension

Alfonso Siani, Paola Russo, Francesco Paolo Cappuccio, Roberto Iacone, Antonella Venezia, Ornella Russo, Gianvincenzo Barba, Licia Iacoviello, Pasquale Strazzullo

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)598-602
Number of pages5
Issue number3
Publication statusPublished - Mar 2004


  • Blood pressure
  • Genes
  • Hypertension
  • Polymorphism
  • Renal circulation
  • Renin-angiotensin-aldosterone system

ASJC Scopus subject areas

  • Internal Medicine


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