The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis
Herraiz-Martínez, Adela (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Llach, Anna (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Tarifa, Carmen (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Gandía, Jorge (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Jiménez-Sábado, Verónica (Institut d'Investigació Biomèdica Sant Pau)
Lozano-Velasco, Estefanía (Universidad de Jaén)
Serra, Selma A. (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Vallmitjana, Alexander (Universitat Politècnica de Catalunya)
Vázquez Ruiz De Castroviejo, Eduardo (Regional Hospital Ciudad de Jaén)
Benítez, Raúl (Universitat Politècnica de Catalunya)
Aránega, Amelia E (Universidad de Jaén)
Muñoz-Guijosa, Christian (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Franco, Diego (Universidad de Jaén)
Cinca, Juan (Institut d'Investigació Biomèdica Sant Pau)
Hove-Madsen, Leif (Institut d'Investigació Biomèdica Sant Pau)
Universitat Autònoma de Barcelona

Date:	2019
Abstract:	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. 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 (I TI) (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 I TI frequency and the increase in the I TI 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. 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.
Grants:	Ministerio de Economía y Competitividad SAF2014-58286-C2-1-R Ministerio de Economía y Competitividad DPI2013-44584-R Ministerio de Economía y Competitividad RD12/0042/0002
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Human atrial myocytes ; Ryanodine receptor ; Sarcoplasmic reticulum calcium release ; Single nucleotide polymorphisms ; Spontaneous electrical activity
Published in:	Cardiovascular research, Vol. 115 Núm. 3 (january 2019) , p. 578-589, ISSN 1755-3245

DOI: 10.1093/cvr/cvy215
PMID: 30219899

12 p, 901.7 KB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles