Synergistic effect of alpha-adducin and ACE genes causes blood pressure changes with body sodium and volume expansion.
BACKGROUND
The genetic dissection of a polygenic, multifactorial, quantitative disease such as arterial hypertension is hampered by a large environmental variance and by genetic heterogeneity.


METHODS
To reduce the environmental variance, we measured the pressor response to a saline load (PRSL) and the basal plasma renin activity (PRA) under very controlled conditions in 145 essential hypertensive patients, as they may have the most direct clinical expression of the putative genetic alteration in renal Na handling and blood pressure (BP) regulation caused by the alpha-adducin and angiotensin-converting enzyme (ACE) polymorphism.


RESULTS
PRSL was smaller in patients homozygous for the wild-type (Gly460) variant of alpha-adducin compared with that of patients bearing at least one copy of the 460Trp variant (2.5 +/- 0.6 vs. 7.0 +/- 0.9 mm Hg, P = 0.0001), whereas the ACE genotype was not associated with differences in PRSL. Both alpha-adducin and ACE affect PRA, with lower values correlated with the number of 460Trp or D alleles (P = 0.019 and 0.017, respectively). Most important, alpha-adducin and ACE interact epistatically in determining the PRSL, doubling the variance explained when epistasis is taken into account (variance from 7.7 to 15.5%).


CONCLUSIONS
These findings support the involvement of ACE and alpha-adducin in PRSL and PRA control, which are of paramount importance in setting the BP level and its response to therapy.
Barlassina
C
C
Nephrology and Postgraduate School of Nephrology, University of Milan, Italy.
Schork
N J
NJ
Manunta
P
P
Citterio
L
L
Sciarrone
M
M
Lanella
G
G
Bianchi
G
G
Cusi
D
D
D000328:Adult; D001794:Blood Pressure / Q000235:genetics*; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D004357:Drug Synergism; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D010641:Phenotype; D010952:Plasma Substitutes / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism*; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D007703:Peptidyl-Dipeptidase A; D010952:Plasma Substitutes; D012964:Sodium; D000099291:Adducins