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 ± 1.0 versus 140.6 ± 0.6 mmHg P = 0.027 and diastolic blood pressure (DBP) 94.2 ± 0.77 versus 92.3 ± 0.5 mmHg, P = 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.
aDivision of Nephrology, Dialysis and Hypertension University ‘Vita-Salute’, IRCCS San Raffaele Hospital, Milano, Italy
bChair of Nephrology, University of Milan, Pediatric Nephrology Unit, Istituti Clinici di Perfezionamento, Milano, Italy
cDepartment of Physiology, School of Medicine, University of Maryland, Baltimore, USA
dResearch Center, Institute of Biology and Biotechnology of Agronomy, CNR
Received 21 May, 2004
Revised 3 November, 2004
Accepted 10 November, 2004
Sponsorship: This work was in part supported by grants from Ministero Universitàe 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: email@example.com