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Genetic polymorphism of the renin–angiotensin–aldosterone system and arterial hypertension in the Italian population: the GENIPER Project

Castellano, Maurizio; Glorioso, Nicola; Cusi, Daniele; Sarzani, Riccardo; Fabris, Bruno; Opocher, Giuseppe; Zoccali, Carmine; Golin, Raffaello; Veglio, Franco; Volpe, Massimo; Mantero, Franco; Fallo, Francesco; Rossi, Gian Paolo; Barlassina, Cristina; Tizzoni, Laura; Filigheddu, Fabiana; Giacchè, Mara; Rossi, Federicaon behalf of the Molecular Genetic Study Group of the Italian Society of Hypertension

Origial papers: Genetic aspects

Objective To detect the association of single polymorphisms of the renin–angiotensin–aldosterone system (RAAS), or different combinations thereof, with hypertension.

Design and methods The GENIPER database is the result of a collaborative effort of 13 Italian research centres to collect genomic DNA in subjects well characterized in terms of blood pressure status. A total of 2461 subjects (normotensive = 611; hypertensive = 1850) were selected and genotyped for the angiotensin-converting enzyme insertion/deletion (ACE I/D), angiotensinogen (AGT) T/C704, angiotensin receptor type 1 (AT1) A/C1166 and aldosterone synthase (ALDO) T/C−344 genetic variants.

Results Allele frequencies were homogeneous over the Italian territory, with the relevant exception of the ACE I/D, the D allele being significantly less frequent in the northern region (61%) than in the rest of the country (67%; P< 0.0001). When comparing allele and genotype distributions in normotensives and hypertensives, the latter presented a small but statistically significant increase of the C allele of AGT T/C704, the A allele of AT1 A/C1166 and the T allele of ALDO T/C−344 polymorphisms (P = 0.018, P = 0.037 and P = 0.015, respectively), with similar trends all over the country. A step-wise logistic regression analysis confirmed these findings, by entering in the model as independent predictors of blood pressure status of AGT T/C704 (P = 0.013), ALDO T/C−344 (P = 0.032) and AT1 A/C1166 polymorphisms (P = 0.075), but not ACE I/D (P = 0.996). We also found some evidence of an additive effect of individual genetic variants of the RAAS, modulating at different levels the same functional pathway, on the risk of developing hypertension, but no synergistic interaction was observed.

Conclusions Our results suggest that some allelic variants of RAAS genes carry a small but identifiable risk of developing arterial hypertension.

Molecular Genetic Study Group, Italian Society of Hypertension.

A complete list of participating investigators and institutions is reported in Appendix 1.

Correspondence and requests for reprints to Prof. Maurizio Castellano (pro tempore coordinator of the GENIPER project), Dipartimento di Scienze Mediche e Chirurgiche, University of Brescia, c/o 2Medicina, Spedali Civili, 25100 Brescia, Italy. Tel. +39 30 3995276; fax +39 30 338 4348; e-mail:

Received 26 November 2002 Revised 16 June 2003 Accepted 17 June 2003

See editorial commentary on page

© 2003 Lippincott Williams & Wilkins, Inc.