ArticleThe Journal of clinical investigation2019
Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 54 citations in OpenAlex.
- A reduced TBX5-dependent gene regulatory network links atrial fibrillation and heart failure.Nature cardiovascular research · 2026Article
- Association of programmed cell death with atrial fibrillation risk: A multi-omics Mendelian randomization study.Medicine · 2026Article
- TBX5 and CHD4 Coordinately Activate Atrial Cardiomyocyte Genes to Maintain Cardiac Rhythm Homeostasis.Circulation · 2025Article
- Single-nuclei multiomics analysis identifies abnormal cardiomyocytes in a murine model of cardiac development.Nature communications · 2025Article
- Secretoneurin plasma levels are decreased after catheter ablation for atrial fibrillation-patients with AF produce lower SN levels than healthy individuals: the SAFE registry.Frontiers in cardiovascular medicine · 2025Article
- A Genomic Link From Heart Failure to Atrial Fibrillation Risk: FOG2 Modulates a TBX5/GATA4-Dependent Atrial Gene Regulatory Network.Circulation · 2024Article
- Gene editing and cardiac disease modelling for the interpretation of genetic variants of uncertain significance in congenital heart disease.Stem cell research & therapy · 2023Article
- Tbx5 maintains atrial identity in post-natal cardiomyocytes by regulating an atrial-specific enhancer network.Nature cardiovascular research · 2023Article
- Fushenmu treatment ameliorates RyR2 with related metabolites in a zebrafish model of barium chloride induced arrhythmia.Chinese medicine · 2023Article
- Article
- Partial and complete loss of myosin binding protein H-like cause cardiac conduction defects.Journal of molecular and cellular cardiology · 2022Article
- Patient-Specific TBX5-G125R Variant Induces Profound Transcriptional Deregulation and Atrial Dysfunction.Circulation · 2022Article
- Modeling Human Cardiac Arrhythmias: Insights from Zebrafish.Journal of cardiovascular development and disease · 2022Review
- Targeting the forkhead box protein P1 pathway as a novel therapeutic approach for cardiovascular diseases.Heart failure reviews · 2022Review
- Review
- Acupuncture as an adjunctive therapy for arrhythmia: a Delphi expert consensus survey.Cardiovascular diagnosis and therapy · 2021Article
- Transcriptional factors in calcium mishandling and atrial fibrillation development.Pflugers Archiv : European journal of physiology · 2021Review
- TBX5-encoded T-box transcription factor 5 variant T223M is associated with long QT syndrome and pediatric sudden cardiac death.American journal of medical genetics. Part A · 2021Article
- Modeling Human TBX5 Haploinsufficiency Predicts Regulatory Networks for Congenital Heart Disease.Developmental cell · 2021Article
- Chamber-specific transcriptional responses in atrial fibrillation.JCI insight · 2020Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
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 Ca2+-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.
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