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European Heart Journal Advance Access published online on January 10, 2009
European Heart Journal, doi:10.1093/eurheartj/ehn572
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

A novel functional haplotype in the human GNAS gene alters G{alpha}s expression, responsiveness to β-adrenoceptor stimulation, and peri-operative cardiac performance

Ulrich H Frey1,2,*, Michael Adamzik1, Eva Kottenberg-Assenmacher1, Heinz Jakob3, Iris Manthey2, Martina Broecker-Preuss4, Lars Bergmann1, Gerd Heusch5, Winfried Siffert2, Jürgen Peters1 and Kirsten Leineweber5

1 Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen, D-45122 Essen, Germany
2 Institut für Pharmakogenetik, Universität Duisburg-Essen, Hufelandstr. 55, D-45122 Essen, Germany
3 Klinik für Herz-Thoraxchirurgie, Universität Duisburg-Essen, D-45122 Essen, Germany
4 Klinik für Endokrinologie, Zentrallabor Bereich Forschung und Lehre, Universität Duisburg-Essen, D-45122 Essen, Germany
5 Institut für Pathophysiologie, Universität Duisburg-Essen, D-45122 Essen, Germany

Received 30 July 2008; revised 4 November 2008; accepted 27 November 2008.

* Corresponding author. Tel: +49 201 723 1401, Fax: +49 201 723 5949, Email: ulrich.frey{at}uk-essen.de

Aims: Cardiac overexpression of the β-adrenoceptor-coupled G-protein subunit G{alpha}s 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 G{alpha}s (GNAS) gene modulate G{alpha}s expression and assessed functional consequences.

Methods and 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 G{alpha}s mRNA expression in homozygous *3 carriers (*3/*3) than in heterozygous (*3/–) and negative *3 (–/–) carriers (P = 0.002). Basal, G{alpha}s- (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).

Conclusion: SNPs in regulatory regions of GNAS impact upon G{alpha}s expression and stimulated cAMP formation in human hearts in vitro and upon cardiac performance in vivo.

Key Words: Heart failure • Molecular biology • Genetics • Cardiac output


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