A novel functional haplotype in the human GNAS gene alters Gαs expression, responsiveness to β-adrenoceptor stimulation, and peri-operative cardiac performance
| Autor: | Heinz Jakob, Lars Bergmann, Eva Kottenberg-Assenmacher, Jürgen Peters, Iris Manthey, Martina Broecker-Preuss, Ulrich H. Frey, Kirsten Leineweber, Gerd Heusch, Winfried Siffert, Michael Adamzik |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male medicine.medical_specialty Gs alpha subunit Adolescent Gene Expression Polymorphism Single Nucleotide Adenylyl cyclase Young Adult chemistry.chemical_compound Internal medicine Receptors Adrenergic beta Gene expression Chromogranins GTP-Binding Protein alpha Subunits Gs GNAS complex locus Humans Medicine Cardiac Output Coronary Artery Bypass Promoter Regions Genetic Forskolin biology Reverse Transcriptase Polymerase Chain Reaction business.industry Haplotype Heterozygote advantage Middle Aged Phenotype Endocrinology Haplotypes chemistry Regulatory sequence biology.protein Female Cardiology and Cardiovascular Medicine business Signal Transduction |
| Zdroj: | European Heart Journal. 30:1402-1410 |
| ISSN: | 1522-9645 0195-668X |
| DOI: | 10.1093/eurheartj/ehn572 |
| Popis: | Aims Cardiac overexpression of the β-adrenoceptor-coupled G-protein subunit Gαs in mice enhances inotropic responses to sympathetic stimulation, but evokes cardiomyopathy with increasing age. We tested whether functional single nucleotide polymorphisms (SNPs) in the human Gαs ( GNAS ) gene modulate Gαs expression and assessed functional consequences. Methods and results Sequencing the promoter and intron 1 of GNAS revealed 11 SNPs resulting in three common haplotypes. Haplotype *3 constructs exhibited significantly higher promoter activity than haplotypes *1 and *2, resulting in a more than 50% higher Gαs mRNA expression in homozygous *3 carriers (\*3/\*3) than in heterozygous (*3/−) and negative *3 (−/−) carriers ( P = 0.002). Basal, Gαs- (via NaF and GTP) and isoproterenol-stimulated adenylyl cyclase (AC) activities were also significantly higher in \*3/\*3 than in *3/− and −/− carriers. In contrast, direct AC activation via forskolin was independent of GNAS haplotypes. Furthermore, haemodynamic measurements in 137 coronary artery bypass patients revealed a higher cardiac index in \*3/\*3 carriers than in *3/− and −/− carriers ( P = 0.025) associated with a lower NYHA functional class ( P = 0.040) and serum NT-proBNP concentrations ( P = 0.002). Conclusion SNPs in regulatory regions of GNAS impact upon Gαs expression and stimulated cAMP formation in human hearts in vitro and upon cardiac performance in vivo . |
| Databáze: | OpenAIRE |
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