A novel functional haplotype in the human GNAS gene alters Galphas expression, responsiveness to beta-adrenoceptor stimulation, and peri-operative cardiac performance.
OBJECTIVE
Cardiac overexpression of the beta-adrenoceptor-coupled G-protein subunit Galphas in mice enhances inotropic responses to sympathetic stimulation, but evokes cardiomyopathy with increasing age. We tested whether functional single nucleotide polymorphisms (SNPs) in the human Galphas (GNAS) gene modulate Galphas expression and assessed functional consequences.


RESULTS
Sequencing the promoter and intron 1 of GNAS revealed 11 SNPs resulting in three common haplotypes. Haplotype *3 constructs exhibited significantly higher promoter activity than haplotypes *1 and *2, resulting in a more than 50% higher Galphas mRNA expression in homozygous *3 carriers (*3/*3) than in heterozygous (*3/-) and negative *3 (-/-) carriers (P = 0.002). Basal, Galphas- (via NaF and GTP) and isoproterenol-stimulated adenylyl cyclase (AC) activities were also significantly higher in *3/*3 than in *3/- and -/- carriers. In contrast, direct AC activation via forskolin was independent of GNAS haplotypes. Furthermore, haemodynamic measurements in 137 coronary artery bypass patients revealed a higher cardiac index in *3/*3 carriers than in *3/- and -/- carriers (P = 0.025) associated with a lower NYHA functional class (P = 0.040) and serum NT-proBNP concentrations (P = 0.002).


CONCLUSIONS
SNPs in regulatory regions of GNAS impact upon Galphas expression and stimulated cAMP formation in human hearts in vitro and upon cardiac performance in vivo.
Frey
Ulrich H
UH
Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen, D-45122 Essen, Germany. ulrich.frey@uk-essen.de
Adamzik
Michael
M
Kottenberg-Assenmacher
Eva
E
Jakob
Heinz
H
Manthey
Iris
I
Broecker-Preuss
Martina
M
Bergmann
Lars
L
Heusch
Gerd
G
Siffert
Winfried
W
Peters
Jürgen
J
Leineweber
Kirsten
K
D000293:Adolescent; D000328:Adult; D002302:Cardiac Output / Q000235:genetics*; D002864:Chromogranins; D001026:Coronary Artery Bypass / Q000379:methods; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011943:Receptors, Adrenergic, beta / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult
D002864:Chromogranins; D011943:Receptors, Adrenergic, beta; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs