Published Online
on February 16, 2004

A more recent version of this article appeared on March 1, 2004

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Submitted on May 7, 2003
Revised on May 29, 2003

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; and Pasquale Strazzullo^*

From Epidemiology & Population Genetics (A.S., P.R., A.V., G.B.), Institute of Food Sciences, CNR, Avellino, Italy; Department of Community Health Sciences (F.P.C.), St. George’s Hospital Medical School, London, UK; Department of Clinical & Experimental Medicine (R.I., O.R., P.S.), Unit of Clinical Genetics and Pharmacology, Hypertension & Mineral Metabolism, "Federico II" University of Naples, Naples, Italy; and "Angela Valenti" Laboratory of Genetic and Environmental Risk Factors for Thrombotic Disease (L.I.), Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.

^* To whom correspondence should be addressed. E-mail: strazzul{at}unina.it.

Abstract--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.

Key words: renal circulation • blood pressure • hypertension • genes • polymorphism • renin-angiotensin-aldosterone system

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