Journal Article

A functional polymorphism of the Gαq (<i>GNAQ</i>) gene is associated with accelerated mortality in African-American heart failure

Stephen B. Liggett, Reagan J. Kelly, Rohan R. Parekh, Scot J. Matkovich, Bonnie J. Benner, Harvey S. Hahn, Faisal M. Syed, Anita S. Galvez, Karen L. Case, Nancy McGuire, Amy M. Odley, Li Sparks, Sharon L.R. Kardia and Gerald W. Dorn

in Human Molecular Genetics

Volume 16, issue 22, pages 2740-2750
Published in print November 2007 | ISSN: 0964-6906
Published online August 2007 | e-ISSN: 1460-2083 | DOI:
A functional polymorphism of the Gαq (GNAQ) gene is associated with accelerated mortality in African-American heart failure

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Gαq, 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 Gαq 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.

Journal Article.  5974 words.  Illustrated.

Subjects: Genetics and Genomics

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