The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis

Author:

Herraiz-Martínez Adela12,Llach Anna23,Tarifa Carmen12,Gandía Jorge1,Jiménez-Sabado Verónica4,Lozano-Velasco Estefanía5,Serra Selma A12,Vallmitjana Alexander6,Vázquez Ruiz de Castroviejo Eduardo7,Benítez Raúl6,Aranega Amelia5,Muñoz-Guijosa Christian8,Franco Diego5,Cinca Juan234,Hove-Madsen Leif124

Affiliation:

1. Biomedical Research Institute Barcelona CSIC-IIBB Antiguo Hospital de la Santa Creu i Sant Pau, Pabellon 11, St Antoni Ma Claret 167, Barcelona, Spain

2. IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

3. Department of Cardiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

4. CIBERCV, Spain

5. Department of Experimental Biology, University of Jaén, Spain

6. Department of Automatic Control, Universitat Politècnica de Catalunya, Barcelona, Spain

7. Cardiology Unit, Regional Hospital Ciudad de Jáen, Spain

8. Department of Cardiac Surgery, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Abstract

Abstract Aims Single 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 results Western 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. Conclusions Here, 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.

Funder

Centro Nacional de Investigaciones Cardiovasculares

Fundació Marató TV3

Spanish Ministry of Economy and Competition

Spanish Ministry of Health

Consume, Instituto de Salud Carlos III

Red de Investigación Cardiovascular

CIBERCV

Fondo Europeo de Desarrollo Regional

FEDER

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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