The α1Na,K-AtPase Locus Plays an Additive Role in Na,K Pump Rate Modulation with Respect to the α-Adducin Gene in Essential Hypertension

Background: The W allele of the G460W α-adducin polymorphism is associated with increased erythrocyte Na transport rates, lower plasma renin activity (PRA) and a greater response to hydrochlorothiazide in North Sardinian patients with essential hypertension. The α1Na,K-ATPase gene microsatellite marker (D1S453 ATP1A1 ) is associated with essential hypertension in the same ethnic group. Objective: We examined whether the D1S453 ATP1A1 marker, alone and in combination with G460W add , is associated with erythrocyte Na transport, PRA and response to hydrochlorothiazide. Methods: D1S453 ATP1A1 (6 alleles) was genotyped in 250 never-treated patients with essential hypertension in whom the G460W add , the erythrocyte Na transporters, PRA and blood pressure (BP) changes after 8 weeks’ hydrochlorothiazide 25 mg/day had been previously studied. Results: In patients with at least one #4 D1S453 allele, compared with patients with no #4 D1S453 alleles, the Na,K pump rate was faster (p < 0.001). In patients with the W460 add genetic background, the D1S453 ATP1A1 #4 allele is associated with a further rise in the Na,K pump rate, compared with the other D1S453 ATP1A1 alleles (p < 0.001). No such effect was shown on the other Na transport systems, nor on the PRA and BP response to diuretic treatment. Conclusions: The D1S453 ATP1A1 may affect the Na,K-pump function both alone and when combined with G460Wadd in essential hypertension. The G460W add /D1S453 ATP1A1 interaction could help in understanding the pathophysiology of hypertension, and represents a further example of the concept that a given gene polymorphism could act selectively on a pertinent intermediate phenotype.