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

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.