Skip Navigation



Human Molecular Genetics Advance Access published online on August 24, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm229
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrowOA All Versions of this Article:
16/22/2740    most recent
ddm229v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Liggett, S. B.
Right arrow Articles by Dorn, G. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Liggett, S. B.
Right arrow Articles by Dorn, G. W.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

A Functional Polymorphism of the G{alpha}q (GNAQ) Gene is Associated with Accelerated Mortality in African American Heart Failure

Stephen B. Liggett1,, Reagan J. Kelly2,, Rohan R. Parekh3, Scot J. Matkovich3, Bonnie J. Benner3, Harvey S. Hahn3, Faisal M. Syed3, Anita S. Galvez3, Karen L. Case3, Nancy McGuire3, Amy M. Odley3, Li Sparks3, Sharon L. R. Kardia2 and Gerald W. Dorn3,*

1 Department of Medicine, Cardiopulmonary Genomics Program, University of Maryland, Baltimore, MD 2 Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 3 Center for Molecular Cardiovascular Research, University of Cincinnati, Cincinnati, OH

* Correspondence to Gerald W Dorn II MD, Hanna Professor and Director, Molecular Cardiovascular Research, 231 Albert Sabin Way, ML 0839, Cincinnati, OH 45267-0839. Phone: 513 558-3065; FAX: 513 558-3438. Email: dorngw{at}ucmail.uc.edu

Received April 25, 2007; Revised July 31, 2007; Accepted July 31, 2007

G{alpha}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 G{alpha}q is implicated in heart disease, we re-sequenced the GNAQ promoter in 1,052 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 basal promoter activity, and adversely affects outcome in human heart failure.

SBL and RJK contributed equally to this manuscript.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Eur Heart JHome page
V. Tikhonoff and E. Casiglia
Evolving concepts of left ventricular hypertrophy
Eur. Heart J., April 1, 2008; 29(7): 846 - 848.
[Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.