Role of the adducin family genes in human essential hypertension.
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.


METHODS
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.
Lanzani
Chiara
C
Division of Nephrology, Dialysis and Hypertension University Vita-Salute, IRCCS San Raffaele Hospital, Milano, Italy. lanzani.chiara@hsr.it
Citterio
Lorena
L
Jankaricova
Maria
M
Sciarrone
M Teresa
MT
Barlassina
Cristina
C
Fattori
Stefania
S
Messaggio
Elisabetta
E
Serio
Clelia Di
CD
Zagato
Laura
L
Cusi
Daniele
D
Hamlyn
John M
JM
Stella
Alessandra
A
Bianchi
Giuseppe
G
Manunta
Paolo
P
D000328:Adult; D018660:Blood Pressure Monitoring, Ambulatory; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D002298:Cardenolides / Q000097:blood; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D005810:Multigene Family / Q000235:genetics*; D011110:Polymorphism, Genetic; D012083:Renin / Q000097:blood; D012503:Saponins / Q000097:blood; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D002298:Cardenolides; D003598:Cytoskeletal Proteins; D012083:Renin; D012503:Saponins; D000099291:Adducins; C501062:ADD2 protein, human; C102021:ADD3 protein, human; C034504:digoxin-like factors