Human Molecular Genetics Advance Access originally published online on August 24, 2007
Human Molecular Genetics 2007 16(22):2740-2750; doi:10.1093/hmg/ddm229
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A functional polymorphism of the G
q (GNAQ) gene is associated with accelerated mortality in African-American heart failure
1 Department of Medicine, Cardiopulmonary Genomics Program, University of Maryland, Baltimore, MD, USA, 2 Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA and 3 Center for Molecular Cardiovascular Research, University of Cincinnati, Cincinnati, OH, USA
* To whom correspondence should be addressed: Hanna Professor and Director, Molecular Cardiovascular Research, 231 Albert Sabin Way, ML 0839, Cincinnati, OH 45267-0839., USA. Tel: +1 5135583065; Fax: +1 5135583438; Email: dorngw{at}ucmail.uc.edu
Received April 25, 2007; Revised July 31, 2007; Accepted July 31, 2007
G
q, encoded by the human GNAQ gene, is an effector subunit of the Gq heterotrimeric G-protein and the convergence point for signaling of multiple Gq-coupled neurohormonal receptors. To identify naturally occurring mutations that could modify GNAQ transcription, we examined genomic DNA isolated from 355 normal subjects for genetic variants in transcription factor binding motifs. Of seven variants identified, the most common was a GC to TT dinucleotide substitution at –694/–695 (allele frequency of 0.467 in Caucasians and 0.329 in African Americans) within a GC-rich domain containing consensus binding sites for Sp-1, c-rel and EGR-1. In promoter–reporter analyses, the TT substitution increased promoter activity in cultured neonatal rat cardiac myocytes and human HEK fibroblasts by 
30% at baseline and after stimulation with phorbol ester. Two other relatively common polymorphisms, –173G/A and –168G/A, did not affect promoter activity. Since altered expression/activity of Gq is implicated in heart disease, we re-sequenced the GNAQ promoter in 1052 prospectively followed heart failure patients. The TT variant was not increased in heart failure, but was associated with decreased survival time among African Americans, with an adjusted RR of death/cardiac transplant of 1.95 (95% CI = 1.21–3.13) for heterozygotes and 2.4 (95% CI = 1.36–4.26) for homozygotes. Gel mobility shift assays showed that this GC/TT substitution eliminated Sp-1 binding without affecting c-rel or EGR-1 binding to this promoter fragment. Thus, the GNAQ –694/–695 promoter polymorphism alters transcription factor binding, increases promoter activity and adversely affects outcome in human heart failure.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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