Association of the G(s)alpha gene with essential hypertension and responseto beta-blockade

We examined whether the GNAS1 locus, encoding the G(s) protein alpha-subuni t (G(s)alpha), is implicated in the genetic causes of essential hypertensio n. A common silent polymorphism (ATT-->ATC, Ile(131)) was identified in exo n 5 of the G(s)alpha gene by single-strand conformation polymorphism analys is and DNA sequencing. This polymorphism consists of the presence (+) or ab sence (-) of a restriction site for FokI. Only 1 other rare allele was foun d in the coding region; the high GC content of the 5' noncoding sequence pr evented mutation scanning of the promoter region of the gene. There was a s ignificant difference in frequency of the FokI alleles between 268 white hy pertensives (FokI+:FokI-, 51%:49%) and a matched group of 231 control subje cts (FokI+:FokI-, 58%:42%) (P=0.02). Multiple regression analysis showed th at the FokI genotype was independently related to the level of untreated sy stolic blood pressure in 294 well-characterized white hypertensives (P=0.01 ) but: not in normotensives. The influence of the FokI allele on blood pres sure (BP) response to beta-blockade was examined in 114 of the patients ran domly assigned to this class of drug. Significant differences in frequency of the FokI allele-were observed in the good responders. (FokI+:FokI--, 62. 5%:37.5%, n=36) versus the poor responders (FokI+-:FokI-, 41.7%:58.3%, n=30 ) after beta-blocker therapy (P=0.02). In a multiple regression analysis, t he G(s)alpha genotype was the only independent predictor of BP response. Th ese results suggest that the GNAS1 locus might carry a functional Variant t hat influences BP variation and response to beta-blockade in essential hype rtension.