title: A novel functional haplotype in the human GNAS gene alters Galphas expression, responsiveness to beta-adrenoceptor stimulation, and peri-operative cardiac performance.
abstract: 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.
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen, D-45122 Essen, Germany. ulrich.frey@uk-essen.de
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: Frey
authors.forename: Michael
authors.initials: M
authors.lastname: Adamzik
authors.forename: Eva
authors.initials: E
authors.lastname: Kottenberg-Assenmacher
authors.forename: Heinz
authors.initials: H
authors.lastname: Jakob
authors.forename: Iris
authors.initials: I
authors.lastname: Manthey
authors.forename: Martina
authors.initials: M
authors.lastname: Broecker-Preuss
authors.forename: Lars
authors.initials: L
authors.lastname: Bergmann
authors.forename: Gerd
authors.initials: G
authors.lastname: Heusch
authors.forename: Winfried
authors.initials: W
authors.lastname: Siffert
authors.forename: Jürgen
authors.initials: J
authors.lastname: Peters
authors.forename: Kirsten
authors.initials: K
authors.lastname: Leineweber
mesh_terms: 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
chemical_list: D002864:Chromogranins; D011943:Receptors, Adrenergic, beta; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs