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European Heart Journal Advance Access originally published online on March 6, 2008
European Heart Journal 2008 29(7):888-897; doi:10.1093/eurheartj/ehm618
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Characterization of the GNAQ promoter and association of increased Gq expression with cardiac hypertrophy in humans

Ulrich H. Frey1,2,*, Wolfgang Lieb3,4, Jeanette Erdmann3, Danai Savidou1, Gerd Heusch5, Kirsten Leineweber5, Heinz Jakob6, Hans-Werner Hense7, Hannelore Löwel8, Norbert H. Brockmeyer9, Heribert Schunkert3 and Winfried Siffert1

1 Institute of Pharmacogenetics, D-45122 Essen, Germany
2 Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, Hufelandstr. 55, D-45122 Essen, Germany
3 Clinic of Internal Medicine II, University Hospital Schleswig-Holstein, Campus Lübeck, Germany
4 Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Lübeck, Germany
5 Institute of Pathophysiology, University Hospital, D-45122 Essen, Germany
6 Department of Cardiothoracic Surgery, University Hospital, D-45122 Essen, Germany
7 Institute of Epidemiology and Social Medicine, D-48149 Münster, Germany
8 GSF-Insitute of Epidemiology, D-85764 Neuherberg, Germany
9 Department of Dermatology and Allergology, Ruhr-University Bochum, D-44791 Bochum, Germany

Received 23 May 2007; revised 10 December 2007; accepted 13 December 2007; online publish-ahead-of-print 6 March 2008.

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

See page 846 for the editorial comment on this article (doi:10.1093/eurheartj/ehn055)

Aims: Transgenic mice with cardiac overexpression of Gq develop cardiac hypertrophy, apoptosis, and heart failure. Similar mechanisms may contribute to human left ventricular hypertrophy (LVH). However, mechanisms regulating transcription of the human GNAQ gene encoding the Gq protein are unknown and single-nucleotide polymorphisms have not been reported.

Methods and results: We delineated essential elements for transcription in the human GNAQ promoter using reporter assays and showed promoter induction by serum and angiotensin II. Sequencing of the whole promoter revealed a common (minor allele frequency 0.48) dinucleotide polymorphism at position –694/–695, resulting in an exchange of two adjacent nucleotides (TT > GC). The GC allele had increased transcription factor binding and was associated with enhanced transcriptional activation by serum or angiotensin II, resulting in enhanced Gq expression and intracellular signalling. Genotyping a population-based survey (n = 1204) revealed a higher prevalence of LVH in individuals with the GC/GC genotype [odds ratio (OR) 4.07; 95% CI 1.63–10.16; P = 0.003], this effect being more pronounced in women (OR 5.52; P = 0.005).

Conclusion: A novel polymorphism in the Gq promoter region is associated with enhanced promoter activity, Gq expression, intracellular signal transduction, and increased prevalence of LVH, particularly in women.

Key Words: G proteins • Polymorphism • Hypertrophy


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