Polymorphisms of α-adducin and salt sensitivity in patients with essential hypertension

Background Abnormalities in renal sodium transport may be involved in hypertension. Adducin, an α/β heterodimeric protein found in the renal tubule is thought to regulate ion transport through changes in the actin cytoskeleton. We investigated whether an α-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 α-adducin locus (20-2500 kb) was done in 137 hypertensive sibling-pairs. 477 hypertensive and 322 normotensive individuals were genotyped for the α-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 α-adducin allele. Findings 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 α-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 monthsʹ 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). Interpretation Our findings of significant linkage of the α-adducin locus to essential hypertension and greater sensitivity to changes in sodium balance among patients with the mutant allele suggest that α-adducin is associated with a salt-sensitive form of essential hypertension. We suggest the α-adducin polymorphism may identify hypertensive patients who will benefit from diuretic treatment or manoeuvres to reduce total body sodium.