Synergistic effect of alpha-adducin and ACE genes causes blood pressure changes with body sodium and volume expansion

Synergistic effect of \u3b1-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 \u3b1-adducin and angiotensin-converting enzyme (ACE) polymorphism. Results PRSL was smaller in patients homozygous for the wild-type (Gly460) variant of \u3b1-adducin compared with that of patients bearing at least one copy of the 460Trp variant (2.5 \ub1 0.6 vs. 7.0 \ub1 0.9 mm Hg, P = 0.0001), whereas the ACE genotype was not associated with differences in PRSL. Both \u3b1-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, \u3b1-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%). Conclusion These findings support the involvement of ACE and \u3b1-adducin in PRSL and PRA control, which are of paramount importance in setting the BP level and its response to therapy

Adducin polymorphism affects renal proximal tubule reabsorption in hypertension

Abnormalities in renal sodium reabsorption may be involved in the development and maintenance of experimental and clinical hypertension. Adducin polymorphism is thought to regulate ion transport in the renal tubule. It has recently been shown that there is a significant linkage of alpha-adducin locus to essential hypertension and that the 460Trp allele is associated with hypertension. Patients with this allele display larger blood pressure changes with body sodium variation. The aim of this study was to test whether alpha-adducin polymorphism is involved in abnormalities of renal function. Because proximal tubular reabsorption has been shown to be tightly coupled to renal perfusion pressure, this segmental tubular function was investigated in 54 (29 Gly/Gly and 25 Gly/Trp) untreated hypertensive patients in basal conditions with the use of endogenous lithium concentration and uric acid. Fractional excretions of lithium and uric acid were significantly decreased in the Gly/Trp hypertensive patients compared with the Gly/Gly hypertensives. The contribution of alpha-adducin to fractional excretion of lithium was investigated by multiple regression analysis. Adducin genotype was significantly (R2=0.11, F=6.5; P<0.01) and directly related to fraction excretion of lithium; gender, age, urinary Na+, urinary uric acid, mean blood pressure, and plasma renin activity were not related. In conclusion, the adducin gene can be considered to be a 'renal hypertensive gene' that modulates the capacity of tubular epithelial cells to transport Na+ and hence contributes to the level of blood pressure