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


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).


CONCLUSIONS
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.
Frey
Ulrich H
UH
Institute of Pharmacogenetics, D-45122 Essen, Germany. ulrich.frey@uk-essen.de
Lieb
Wolfgang
W
Erdmann
Jeanette
J
Savidou
Danai
D
Heusch
Gerd
G
Leineweber
Kirsten
K
Jakob
Heinz
H
Hense
Hans-Werner
HW
Löwel
Hannelore
H
Brockmeyer
Norbert H
NH
Schunkert
Heribert
H
Siffert
Winfried
W
D000328:Adult; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D005838:Genotype; D006333:Heart Failure / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics
D019204:GTP-Binding Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11