Role of the adducin family genes in human essential hypertension Chiara Lanzani a , Lorena Citterio a , Maria Jankaricova a , M. Teresa Sciarrone a , Cristina Barlassina b , Stefania Fattori a , Elisabetta Messaggio a , Clelia Di Serio a , Laura Zagato a , Daniele Cusi b , John M. Hamlyn c , Alessandra Stella d , Giuseppe Bianchi a and Paolo Manunta a Objective In both humans and rats, polymorphisms of the alpha adducin (ADD1) gene are involved in renal sodium handling, essential hypertension and some of its organ complications. Adducin functions within cells as a heterodimer composed of various combinations of three subunits that are coded by three genes (ADD1, 2, 3) each located on a different chromosome. Design These characteristics provide the biochemical basis for investigating epistatic interactions among these loci. Methods We examined the three adducin gene polymorphisms and their association with ambulatory blood pressure (ABPM) and with plasma levels of renin activity (PRA), endogenous ouabain (EO), in 512 newly discovered and never-treated hypertensive patients. Results Relative to carriers of the wild type (Gly/Gly) ADD1 gene, patients carrying the mutated Trp ADD1 allele had higher blood pressure (systolic blood pressure (SBP) 143.2 W 1.0 versus 140.6 W 0.6 mmHg P U 0.027 and diastolic blood pressure (DBP) 94.2 W 0.77 versus 92.3 W 0.5 mmHg, P U 0.03), lower PRA and EO, consistent with the hypothesis of the renal sodium retaining effect of the Trp allele. Polymorphisms in the ADD2 and ADD3 genes taken alone were not associated with these variables. However, the differences in SBP and DBP between the two ADD1 genotypes were greatest in carriers of the ADD3 G allele (around + 8 mmHg). The significance of the interaction between ADD1 and ADD3 ranged between P = 0.020 to P = 0.006 according to the genetic model applied. Conclusions The interaction of ADD1 and ADD3 gene variants in humans is statistically associated with variation in blood pressure, suggesting the presence of epistatic effects among these loci. J Hypertens 23:543–549 Q 2005 Lippincott Williams & Wilkins. Journal of Hypertension 2005, 23:543–549 Keywords: adducin, genetics, kidney a Division of Nephrology, Dialysis and Hypertension University ‘Vita-Salute’, IRCCS San Raffaele Hospital, Milano, Italy, b Chair of Nephrology, University of Milan, Pediatric Nephrology Unit, Istituti Clinici di Perfezionamento, Milano, Italy, c Department of Physiology, School of Medicine, University of Maryland, Baltimore, USA and d Research Center, Institute of Biology and Biotechnology of Agronomy, CNR. Sponsorship: This work was in part supported by grants from Ministero Universita ` e Ricerca Scientifica of Italy (FIRB Grant RBNE01724C_002 to D.C., PRIN Grant 2002067759_006 to C.B., PRIN Grant 2002067759_001 to G.B.), from Eurnetgen, EC funded research (Grant QLG1-2000-01137) and by a grant of the Ministry of Health of Italy (ICS 030.6/RF00-49). Correspondence and requests for reprints to Chiara Lanzani, Division of Nephrology, Dialysis and Hypertension, University ‘Vita-Salute’, San Raffaele, IRCCS San Raffaele Hospital, Via Olgettina 60, 20132 Milan, Italy. Tel: +39 02 2643 3006; fax: +39 02 2643 2384; e-mail: lanzani.chiara@hsr.it Received 21 May 2004 Revised 3 November 2004 Accepted 10 November 2004 Introduction Attempts to define the impact of a given candidate gene polymorphism in polygenetic multifactorial cardiovascu- lar diseases like hypertension and its cardiovascular and renal complications have yielded contrary inferences [1,2]. The results concerning the a-adducin polymorph- ism (ADD1) have suffered in a similar manner. Namely, after the first positive findings [3], mixed results were obtained across populations [4]. The causes of this incon- sistency have been discussed in detail elsewhere [2,5], but context dependency either genetic or environmental is the most important cause [6]. Many recent observations support the original proposal that the polymorphism of ADD1 taken alone or in combination with those of ADD2, and angiotensin- converting enzyme (ACE) is associated either with hypertension or with the cardiac, vascular and renal complication relevant to its development [7–13]. The cellular basis of the cardiovascular impact of adducin has been previously provided [14]. Adducin functions within the cell as a heterodimer that is formed by various combinations, of a, b and g subunits, each coded by genes (ADD1, ADD2 and ADD3, respec- tively) that are located on different chromosomes [15,16]. The three genes are differentially expressed in a devel- opmental and tissue-specific manner, and may coexist as a-b and/or a-g heterodimers [16]. The functional char- acteristics of the heterodimer within cells are the result of 543 0263-6352 ß 2005 Lippincott Williams & Wilkins