RGD Reference Report - A functional polymorphism of the Galphaq (GNAQ) gene is associated with accelerated mortality in African-American heart failure. - Rat Genome Database

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A functional polymorphism of the Galphaq (GNAQ) gene is associated with accelerated mortality in African-American heart failure.

Authors: Liggett, Stephen B  Kelly, Reagan J  Parekh, Rohan R  Matkovich, Scot J  Benner, Bonnie J  Hahn, Harvey S  Syed, Faisal M  Galvez, Anita S  Case, Karen L  McGuire, Nancy  Odley, Amy M  Sparks, Li  Kardia, Sharon L R  Dorn, Gerald W 
Citation: Liggett SB, etal., Hum Mol Genet. 2007 Nov 15;16(22):2740-50. doi: 10.1093/hmg/ddm229. Epub 2007 Aug 24.
RGD ID: 126781754
Pubmed: PMID:17720980   (View Abstract at PubMed)
DOI: DOI:10.1093/hmg/ddm229   (Journal Full-text)

Galphaq, 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 approximately 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 Galphaq 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GNAQHumancongestive heart failure disease_progressionIAGP DNA:polymorphism:promoter:[-694C>T;-695G>T] (human)RGD 
GNAQHumancongestive heart failure no_associationIAGP DNA:polymorphisms:promoter:multipleRGD 
GnaqRatcongestive heart failure disease_progressionISOGNAQ (Homo sapiens)DNA:polymorphism:promoter:[-694C>T;-695G>T] (human)RGD 
GnaqRatcongestive heart failure no_associationISOGNAQ (Homo sapiens)DNA:polymorphisms:promoter:multipleRGD 
GnaqMousecongestive heart failure disease_progressionISOGNAQ (Homo sapiens)DNA:polymorphism:promoter:[-694C>T;-695G>T] (human)RGD 
GnaqMousecongestive heart failure no_associationISOGNAQ (Homo sapiens)DNA:polymorphisms:promoter:multipleRGD 

Objects Annotated

Genes (Rattus norvegicus)
Gnaq  (G protein subunit alpha q)

Genes (Mus musculus)
Gnaq  (guanine nucleotide binding protein, alpha q polypeptide)

Genes (Homo sapiens)
GNAQ  (G protein subunit alpha q)


Additional Information