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

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2004-03, Vol.43 (3), p.598-602
• Main Authors: Siani, Alfonso, Russo, Paola, Paolo Cappuccio, Francesco, Iacone, Roberto, Venezia, Antonella, Russo, Ornella, Barba, Gianvincenzo, Iacoviello, Licia, Strazzullo, Pasquale
• Format: Article
• Language: English
• Subjects: Adult; Aged; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Endocrine kidney. Renin-angiotensin-aldosterone system; Fundamental and applied biological sciences. Psychology; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Hypertension - genetics; Hypertension - metabolism; Hypertension - urine; Kidney Tubules, Proximal - metabolism; Lithium - urine; Male; Medical sciences; Middle Aged; Polymorphism, Genetic; Renin-Angiotensin System - genetics; Sodium - metabolism; Sodium - urine; Uric Acid - urine; Vertebrates: endocrinology
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.0000117985.57001.b3

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 polymorphismsI/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 (OR3.4 [(99% CI1.1 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.