Association of the G(s)alpha gene with essential hypertension and response to beta-blockade.
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.
Jia
H
H
Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. h.jiia@ucl.ac.uk
Hingorani
A D
AD
Sharma
P
P
Hopper
R
R
Dickerson
C
C
Trutwein
D
D
Lloyd
D D
DD
Brown
M J
MJ
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D018807:Polymorphism, Single-Stranded Conformational
D000319:Adrenergic beta-Antagonists; D019205:GTP-Binding Protein alpha Subunits, Gs