ArticleCardiovascular research2019
The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis.
Article in Cardiovascular research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 43 citations in OpenAlex.
- Multiple 4q25 risk variants impair calcium homeostasis and compromise left atrial function.Cardiovascular research · 2026Article
- Transforming atrial fibrillation management by targeting comorbidities and reducing atrial fibrillation burden: the 10th AFNET/EHRA consensus conference.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2025Article
- Single-Nucleotide Polymorphisms,International journal of molecular sciences · 2025Review
- Prevalence of Genetic Variants Associated with Atrial Fibrillation Risk in the Asymptomatic Young Adult Population.Medicina (Kaunas, Lithuania) · 2025Article
- Oxidative Stress Causes Mitochondrial and Electrophysiologic Dysfunction to Promote Atrial Fibrillation inCirculation. Arrhythmia and electrophysiology · 2025Article
- Decreased METTL3 in atrial myocytes promotes atrial fibrillation.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2025Article
- Impact of Overnight Storage of Human Atrial Myocytes on Intracellular Calcium Homeostasis and Electrophysiological Utility.Biomolecules · 2024Article
- Atrial fibrillation: pathophysiology, genetic and epigenetic mechanisms.The Lancet regional health. Europe · 2024Review
- hiPSC-derived cardiomyocytes as a model to study the role of small-conductance CaFrontiers in cell and developmental biology · 2024Review
- The selective RyR2 inhibitor ent-verticilide suppresses atrial fibrillation susceptibility caused by Pitx2 deficiency.Journal of molecular and cellular cardiology · 2023Article
- Expression and Impact of Adenosine AInternational journal of molecular sciences · 2023Article
- Spatial Distribution of Calcium Sparks Determines Their Ability to Induce Afterdepolarizations in Human Atrial Myocytes.JACC. Basic to translational science · 2023Article
- Impact of R-Carvedilol on β2-Adrenergic Receptor-Mediated Spontaneous Calcium Release in Human Atrial Myocytes.Biomedicines · 2022Article
- Genetic and non-genetic risk factors associated with atrial fibrillation.Life sciences · 2022Review
- Influence of sex on intracellular calcium homoeostasis in patients with atrial fibrillation.Cardiovascular research · 2022Article
- Atrial fibrillation and atrial cardiomyopathies.Journal of cardiovascular electrophysiology · 2021Review
- Understanding PITX2-Dependent Atrial Fibrillation Mechanisms through Computational Models.International journal of molecular sciences · 2021Review
- In Silico Assessment of Class I Antiarrhythmic Drug Effects onInternational journal of molecular sciences · 2021Article
- Mechanisms underlying pro-arrhythmic abnormalities arising from Pitx2-induced electrical remodelling: an in silico intersubject variability study.Annals of translational medicine · 2021Article
- Overexpression of MiR-29b-3p Inhibits Atrial Remodeling in Rats by Targeting PDGF-B Signaling Pathway.Oxidative medicine and cellular longevity · 2021Article
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Authors and funding
15 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsSingle nucleotide polymorphisms on chromosome 4q25 have been associated with risk of atrial fibrillation (AF) but the exiguous knowledge of the mechanistic links between these risk variants and underlying electrophysiological alterations hampers their clinical utility. Here, we tested the hypothesis that 4q25 risk variants cause alterations in the intracellular calcium homoeostasis that predispose to spontaneous electrical activity. METHODS AND
resultsWestern blotting, confocal calcium imaging, and patch-clamp techniques were used to identify mechanisms linking the 4q25 risk variants rs2200733T and rs13143308T to defects in the calcium homoeostasis in human atrial myocytes. Our findings revealed that the rs13143308T variant was more frequent in patients with AF and that myocytes from carriers of this variant had a significantly higher density of calcium sparks (14.1 ± 4.5 vs. 3.1 ± 1.3 events/min, P = 0.02), frequency of transient inward currents (ITI) (1.33 ± 0.24 vs. 0.26 ± 0.09 events/min, P < 0.001) and incidence of spontaneous membrane depolarizations (1.22 ± 0.26 vs. 0.56 ± 0.17 events/min, P = 0.001) than myocytes from patients with the normal rs13143308G variant. These alterations were linked to higher sarcoplasmic reticulum calcium loading (10.2 ± 1.4 vs. 7.3 ± 0.5 amol/pF, P = 0.01), SERCA2 expression (1.37 ± 0.13 fold, P = 0.03), and RyR2 phosphorylation at ser2808 (0.67 ± 0.08 vs. 0.47 ± 0.03, P = 0.01) but not at ser2814 (0.28 ± 0.14 vs. 0.31 ± 0.14, P = 0.61) in patients carrying the rs13143308T risk variant. Furthermore, the presence of a risk variant or AF independently increased the ITI frequency and the increase in the ITI frequency observed in carriers of the risk variants was exacerbated in those with AF. By contrast, the presence of a risk variant did not affect the amplitude or properties of the L-type calcium current in patients with or without AF.
conclusionsHere, we identify the 4q25 variant rs13143308T as a genetic risk marker for AF, specifically associated with excessive calcium release and spontaneous electrical activity linked to increased SERCA2 expression and RyR2 phosphorylation.
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