We examined whether the GNAS1 locus, encoding the G(s) protein alpha-subunit (G(s)alpha), is implicated in the genetic causes of essential hypertension. A common silent polymorphism (ATT-->ATC, Ile(131)) was identified in exon 5 of the G(s)alpha gene by single-strand conformation polymorphism analysis and DNA sequencing. This polymorphism consists of the presence (+) or absence (-) of a restriction site for FokI. Only 1 other rare allele was found in the coding region; the high GC content of the 5' noncoding sequence prevented mutation scanning of the promoter region of the gene. There was a significant difference in frequency of the FokI alleles between 268 white hypertensives (FokI+:FokI-, 51%:49%) and a matched group of 231 control subjects (FokI+:FokI-, 58%:42%) (P=0.02). Multiple regression analysis showed that the FokI genotype was independently related to the level of untreated systolic blood pressure in 294 well-characterized white hypertensives (P=0.01) but not in normotensives. The influence of the FokI allele on blood pressure (BP) response to beta-blockade was examined in 114 of the patients randomly 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, the G(s)alpha genotype was the only independent predictor of BP response. These results suggest that the GNAS1 locus might carry a functional variant that influences BP variation and response to beta-blockade in essential hypertension.