Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension.
BACKGROUND
Abnormalities in renal sodium transport may be involved in hypertension. Adducin, an alpha/beta heterodimeric protein found in the renal tubule is thought to regulate ion transport through changes in the actin cytoskeleton. We investigated whether an alpha-adducin polymorphism (Gly 460 Trp) is involved in essential hypertension in two separate populations.


METHODS
Linkage analysis of three DNA markers at different distances from the alpha-adducin locus (20-2500 kb) was done in 137 hypertensive sibling-pairs. 477 hypertensive and 322 normotensive individuals were genotyped for the alpha-adducin polymorphism. The blood-pressure response to acute and chronic changes in sodium balance was studied in hypertensive individuals with and without the 460 Trp alpha-adducin allele.


RESULTS
Significant linkage was found for all three markers in the sibling-pair study. The extra shared alleles (9.1%, 6.5%, and 4.7%) and the significance level for linkage (p = 0.0006, p = 0.0119, and p = 0.0211) both decreased with increasing distance from the alpha-adducin locus. There was a significant association between the 460 Trp mutation and hypertension (p = 0.0003). In the salt-sensitivity test, to assess the acute blood-pressure response to changes in body sodium in 86 hypertensive patients, the decrease in mean arterial pressure was greater in 65 patients who were heterozygous for the mutant allele (Gly/Trp) than in 21 wild-type homozygotes (Gly/Gly) (mean decrease 15.9 [SE 2.0] vs 7.4 [1.3] mm Hg; p = 0.001). Similarly, 21 heterozygous hypertensive patients showed a greater fall in mean arterial pressure in response to 2 months' treatment with hydrochlorothiazide than did 37 wild-type homozygous hypertensive patients (mean decrease 14.7 [2.2] vs 6.8 [1.4] mm Hg; p = 0.002).


CONCLUSIONS
Our findings of significant linkage of the alpha-adducin locus to essential hypertension and greater sensitivity to changes in sodium balance among patients with the mutant allele suggest that alpha-adducin is associated with a salt-sensitive form of essential hypertension. We suggest the alpha-adducin polymorphism may identify hypertensive patients who will benefit from diuretic treatment or manoeuvres to reduce total body sodium.
Cusi
D
D
Postgraduate School of Nephrology, University of Milan, Italy.
Barlassina
C
C
Azzani
T
T
Casari
G
G
Citterio
L
L
Devoto
M
M
Glorioso
N
N
Lanzani
C
C
Manunta
P
P
Righetti
M
M
Rivera
R
R
Stella
P
P
Troffa
C
C
Zagato
L
L
Bianchi
G
G
D000368:Aged; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D005602:France; D005787:Gene Frequency; D006580:Genetic Carrier Screening; D005819:Genetic Markers; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic; D017673:Sodium Chloride, Dietary / Q000009:adverse effects* / Q000378:metabolism; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D005819:Genetic Markers; D017673:Sodium Chloride, Dietary; D000099291:Adducins