Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis
| Autor: | Christopher R. Weber, Kaitlyn M Shen, Michael Broman, Margaret Gadek, Leonid Tyan, Ivan P. Moskowitz, Wenli Dai, Brigitte Laforest, Sonja Lazarevic |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Ryanodine receptor 2 Mice 03 medical and health sciences 0302 clinical medicine Risk Factors Internal medicine Atrial Fibrillation Calcium flux medicine Animals Homeostasis Humans Calcium Signaling Heart Atria GATA4 business.industry Calcium channel Cardiac arrhythmia Atrial fibrillation General Medicine medicine.disease Phospholamban Sarcoplasmic Reticulum 030104 developmental biology Endocrinology Genetic Loci 030220 oncology & carcinogenesis cardiovascular system Calcium Haploinsufficiency business Genome-Wide Association Study Transcription Factors Research Article |
| Zdroj: | Journal of Clinical Investigation. 129:4937-4950 |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | Atrial fibrillation (AF), defined by disorganized atrial cardiac rhythm, is the most prevalent cardiac arrhythmia worldwide. Recent genetic studies have highlighted a major heritable component and identified numerous loci associated with AF risk, including the cardiogenic transcription factor genes TBX5, GATA4, and NKX2-5. We report that Tbx5 and Gata4 interact with opposite signs for atrial rhythm controls compared with cardiac development. Using mouse genetics, we found that AF pathophysiology caused by Tbx5 haploinsufficiency, including atrial arrhythmia susceptibility, prolonged action potential duration, and ectopic cardiomyocyte depolarizations, were all rescued by Gata4 haploinsufficiency. In contrast, Nkx2-5 haploinsufficiency showed no combinatorial effect. The molecular basis of the TBX5/GATA4 interaction included normalization of intra-cardiomyocyte calcium flux and expression of calcium channel genes Atp2a2 and Ryr2. Furthermore, GATA4 and TBX5 showed antagonistic interactions on an Ryr2 enhancer. Atrial rhythm instability caused by Tbx5 haploinsufficiency was rescued by a decreased dose of phospholamban, a sarco/endoplasmic reticulum Ca(2+)-ATPase inhibitor, consistent with a role for decreased sarcoplasmic reticulum calcium flux in Tbx5-dependent AF susceptibility. This work defines a link between Tbx5 dose, sarcoplasmic reticulum calcium flux, and AF propensity. The unexpected interactions between Tbx5 and Gata4 in atrial rhythm control suggest that evaluating specific interactions between genetic risk loci will be necessary for ascertaining personalized risk from genetic association data. |
| Databáze: | OpenAIRE |
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