Association of the G s α Gene With Essential Hypertension and Response to β-Blockade

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Abstract
—We examined whether the GNAS1 locus, encoding the G s protein α-subunit (G s α), 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 α gene by single-strand conformation polymorphism analysis and DNA sequencing. This polymorphism consists of the presence (+) or absence (−) of a restriction site for Fok I. 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 Fok I alleles between 268 white hypertensives ( Fok I+: Fok I−, 51%:49%) and a matched group of 231 control subjects ( Fok I+: Fok I−, 58%:42%) ( P =0.02). Multiple regression analysis showed that the Fok I 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 Fok I allele on blood pressure (BP) response to β-blockade was examined in 114 of the patients randomly assigned to this class of drug. Significant differences in frequency of the Fok I allele were observed in the good responders ( Fok I+: Fok I−, 62.5%:37.5%, n=36) versus the poor responders ( Fok I+: Fok I−, 41.7%:58.3%, n=30) after β-blocker therapy ( P =0.02). In a multiple regression analysis, the G s α genotype was the only independent predictor of BP response. These results suggest that the GNAS 1 locus might carry a functional variant that influences BP variation and response to β-blockade in essential hypertension.