The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis
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...
Gespeichert in:
| Veröffentlicht in: | Cardiovascular research 2019-03, Vol.115 (3), p.578-589 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 589 |
|---|---|
| container_issue | 3 |
| container_start_page | 578 |
| container_title | Cardiovascular research |
| container_volume | 115 |
| creator | Herraiz-Martínez, Adela Llach, Anna Tarifa, Carmen Gandía, Jorge Jiménez-Sabado, Verónica Lozano-Velasco, Estefanía Serra, Selma A Vallmitjana, Alexander Vázquez Ruiz de Castroviejo, Eduardo Benítez, Raúl Aranega, Amelia Muñoz-Guijosa, Christian Franco, Diego Cinca, Juan Hove-Madsen, Leif |
| description | 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 |
| doi_str_mv | 10.1093/cvr/cvy215 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6383060</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/cvr/cvy215</oup_id><sourcerecordid>2108248269</sourcerecordid><originalsourceid>FETCH-LOGICAL-c476t-eeaa2ea93e27ff2db0d0a38e191c9993c522bc75fd5c2d59b5ee85626e9e3cde3</originalsourceid><addsrcrecordid>eNp9kUtr3DAURkVJyEwem_yAok2gBJzoYcnWplBC0hYC2UzXiixfd5SxrYkkD-TfR9OZDu0mi4u46Nyjx4fQJSU3lCh-azch1xuj4hOa00qIgrNSHKE5IaQuJJd8hk5jfMmtEFV5gmacMKpqpeboebEEXL4ygTcmODMmHCLltOSc1Avcu3EVcXBxhX2HTcpEjzvXBNf3Jjk_4uRxCx3Y5DaAremtmwa89IMHH5OJLp6j4870ES726xn69XC_uPtRPD59_3n37bGwZSVTAWAMA6M4sKrrWNuQlhheA1XUKqW4FYw1thJdKyxrhWoEQC0kk6CA2xb4Gfq6866nZoDWwpiC6fU6uMGEN-2N0__vjG6pf_uNlrzmRJIsoDuBjZPVASwEa9KfwUOzLUYqprlUJdnOfNkfGvzrBDHpwUUL-XNG8FPUjJKalTWTKqPXe33wMQboDlejRG9j1DlGvYsxw5__fcwB_ZtbBq52gJ_WH4neAY_qp7E</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2108248269</pqid></control><display><type>article</type><title>The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>MEDLINE</source><source>Recercat</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Herraiz-Martínez, Adela ; Llach, Anna ; Tarifa, Carmen ; Gandía, Jorge ; Jiménez-Sabado, Verónica ; Lozano-Velasco, Estefanía ; Serra, Selma A ; Vallmitjana, Alexander ; Vázquez Ruiz de Castroviejo, Eduardo ; Benítez, Raúl ; Aranega, Amelia ; Muñoz-Guijosa, Christian ; Franco, Diego ; Cinca, Juan ; Hove-Madsen, Leif</creator><creatorcontrib>Herraiz-Martínez, Adela ; Llach, Anna ; Tarifa, Carmen ; Gandía, Jorge ; Jiménez-Sabado, Verónica ; Lozano-Velasco, Estefanía ; Serra, Selma A ; Vallmitjana, Alexander ; Vázquez Ruiz de Castroviejo, Eduardo ; Benítez, Raúl ; Aranega, Amelia ; Muñoz-Guijosa, Christian ; Franco, Diego ; Cinca, Juan ; Hove-Madsen, Leif</creatorcontrib><description>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.</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1093/cvr/cvy215</identifier><identifier>PMID: 30219899</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Action Potentials - genetics ; Aged ; Atrial Fibrillation - diagnosis ; Atrial Fibrillation - genetics ; Atrial Fibrillation - metabolism ; Atrial Fibrillation - physiopathology ; Calcium - metabolism ; Calcium Signaling - genetics ; Cardiologia ; Case-Control Studies ; Chromosomes, Human, Pair 4 ; Electrònica biomèdica ; Electrònica en cardiologia ; Enginyeria biomèdica ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Heart Atria - metabolism ; Heart Atria - physiopathology ; Heart Rate - genetics ; Homeostasis ; Human atrial myocytes ; Humans ; Informàtica ; Male ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; Original ; Phenotype ; Phosphorylation ; Polymorphism, Single Nucleotide ; Risk Factors ; Ryanodine receptor ; Ryanodine Receptor Calcium Release Channel - metabolism ; Sarcoplasmic reticulum calcium release ; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism ; Single nucleotide polymorphisms ; Spontaneous electrical activity ; Àrees temàtiques de la UPC</subject><ispartof>Cardiovascular research, 2019-03, Vol.115 (3), p.578-589</ispartof><rights>The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology 2018</rights><rights>The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.</rights><rights>Attribution-NonCommercial-NoDerivs 3.0 Spain info:eu-repo/semantics/openAccess <a href="http://creativecommons.org/licenses/by-nc-nd/3.0/es/">http://creativecommons.org/licenses/by-nc-nd/3.0/es/</a></rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c476t-eeaa2ea93e27ff2db0d0a38e191c9993c522bc75fd5c2d59b5ee85626e9e3cde3</citedby><cites>FETCH-LOGICAL-c476t-eeaa2ea93e27ff2db0d0a38e191c9993c522bc75fd5c2d59b5ee85626e9e3cde3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,1578,26951,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30219899$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Herraiz-Martínez, Adela</creatorcontrib><creatorcontrib>Llach, Anna</creatorcontrib><creatorcontrib>Tarifa, Carmen</creatorcontrib><creatorcontrib>Gandía, Jorge</creatorcontrib><creatorcontrib>Jiménez-Sabado, Verónica</creatorcontrib><creatorcontrib>Lozano-Velasco, Estefanía</creatorcontrib><creatorcontrib>Serra, Selma A</creatorcontrib><creatorcontrib>Vallmitjana, Alexander</creatorcontrib><creatorcontrib>Vázquez Ruiz de Castroviejo, Eduardo</creatorcontrib><creatorcontrib>Benítez, Raúl</creatorcontrib><creatorcontrib>Aranega, Amelia</creatorcontrib><creatorcontrib>Muñoz-Guijosa, Christian</creatorcontrib><creatorcontrib>Franco, Diego</creatorcontrib><creatorcontrib>Cinca, Juan</creatorcontrib><creatorcontrib>Hove-Madsen, Leif</creatorcontrib><title>The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>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.</description><subject>Action Potentials - genetics</subject><subject>Aged</subject><subject>Atrial Fibrillation - diagnosis</subject><subject>Atrial Fibrillation - genetics</subject><subject>Atrial Fibrillation - metabolism</subject><subject>Atrial Fibrillation - physiopathology</subject><subject>Calcium - metabolism</subject><subject>Calcium Signaling - genetics</subject><subject>Cardiologia</subject><subject>Case-Control Studies</subject><subject>Chromosomes, Human, Pair 4</subject><subject>Electrònica biomèdica</subject><subject>Electrònica en cardiologia</subject><subject>Enginyeria biomèdica</subject><subject>Female</subject><subject>Genetic Association Studies</subject><subject>Genetic Predisposition to Disease</subject><subject>Heart Atria - metabolism</subject><subject>Heart Atria - physiopathology</subject><subject>Heart Rate - genetics</subject><subject>Homeostasis</subject><subject>Human atrial myocytes</subject><subject>Humans</subject><subject>Informàtica</subject><subject>Male</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - pathology</subject><subject>Original</subject><subject>Phenotype</subject><subject>Phosphorylation</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Risk Factors</subject><subject>Ryanodine receptor</subject><subject>Ryanodine Receptor Calcium Release Channel - metabolism</subject><subject>Sarcoplasmic reticulum calcium release</subject><subject>Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism</subject><subject>Single nucleotide polymorphisms</subject><subject>Spontaneous electrical activity</subject><subject>Àrees temàtiques de la UPC</subject><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><sourceid>XX2</sourceid><recordid>eNp9kUtr3DAURkVJyEwem_yAok2gBJzoYcnWplBC0hYC2UzXiixfd5SxrYkkD-TfR9OZDu0mi4u46Nyjx4fQJSU3lCh-azch1xuj4hOa00qIgrNSHKE5IaQuJJd8hk5jfMmtEFV5gmacMKpqpeboebEEXL4ygTcmODMmHCLltOSc1Avcu3EVcXBxhX2HTcpEjzvXBNf3Jjk_4uRxCx3Y5DaAremtmwa89IMHH5OJLp6j4870ES726xn69XC_uPtRPD59_3n37bGwZSVTAWAMA6M4sKrrWNuQlhheA1XUKqW4FYw1thJdKyxrhWoEQC0kk6CA2xb4Gfq6866nZoDWwpiC6fU6uMGEN-2N0__vjG6pf_uNlrzmRJIsoDuBjZPVASwEa9KfwUOzLUYqprlUJdnOfNkfGvzrBDHpwUUL-XNG8FPUjJKalTWTKqPXe33wMQboDlejRG9j1DlGvYsxw5__fcwB_ZtbBq52gJ_WH4neAY_qp7E</recordid><startdate>20190301</startdate><enddate>20190301</enddate><creator>Herraiz-Martínez, Adela</creator><creator>Llach, Anna</creator><creator>Tarifa, Carmen</creator><creator>Gandía, Jorge</creator><creator>Jiménez-Sabado, Verónica</creator><creator>Lozano-Velasco, Estefanía</creator><creator>Serra, Selma A</creator><creator>Vallmitjana, Alexander</creator><creator>Vázquez Ruiz de Castroviejo, Eduardo</creator><creator>Benítez, Raúl</creator><creator>Aranega, Amelia</creator><creator>Muñoz-Guijosa, Christian</creator><creator>Franco, Diego</creator><creator>Cinca, Juan</creator><creator>Hove-Madsen, Leif</creator><general>Oxford University Press</general><scope>TOX</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>XX2</scope><scope>5PM</scope></search><sort><creationdate>20190301</creationdate><title>The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis</title><author>Herraiz-Martínez, Adela ; Llach, Anna ; Tarifa, Carmen ; Gandía, Jorge ; Jiménez-Sabado, Verónica ; Lozano-Velasco, Estefanía ; Serra, Selma A ; Vallmitjana, Alexander ; Vázquez Ruiz de Castroviejo, Eduardo ; Benítez, Raúl ; Aranega, Amelia ; Muñoz-Guijosa, Christian ; Franco, Diego ; Cinca, Juan ; Hove-Madsen, Leif</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c476t-eeaa2ea93e27ff2db0d0a38e191c9993c522bc75fd5c2d59b5ee85626e9e3cde3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Action Potentials - genetics</topic><topic>Aged</topic><topic>Atrial Fibrillation - diagnosis</topic><topic>Atrial Fibrillation - genetics</topic><topic>Atrial Fibrillation - metabolism</topic><topic>Atrial Fibrillation - physiopathology</topic><topic>Calcium - metabolism</topic><topic>Calcium Signaling - genetics</topic><topic>Cardiologia</topic><topic>Case-Control Studies</topic><topic>Chromosomes, Human, Pair 4</topic><topic>Electrònica biomèdica</topic><topic>Electrònica en cardiologia</topic><topic>Enginyeria biomèdica</topic><topic>Female</topic><topic>Genetic Association Studies</topic><topic>Genetic Predisposition to Disease</topic><topic>Heart Atria - metabolism</topic><topic>Heart Atria - physiopathology</topic><topic>Heart Rate - genetics</topic><topic>Homeostasis</topic><topic>Human atrial myocytes</topic><topic>Humans</topic><topic>Informàtica</topic><topic>Male</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Myocytes, Cardiac - pathology</topic><topic>Original</topic><topic>Phenotype</topic><topic>Phosphorylation</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Risk Factors</topic><topic>Ryanodine receptor</topic><topic>Ryanodine Receptor Calcium Release Channel - metabolism</topic><topic>Sarcoplasmic reticulum calcium release</topic><topic>Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism</topic><topic>Single nucleotide polymorphisms</topic><topic>Spontaneous electrical activity</topic><topic>Àrees temàtiques de la UPC</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Herraiz-Martínez, Adela</creatorcontrib><creatorcontrib>Llach, Anna</creatorcontrib><creatorcontrib>Tarifa, Carmen</creatorcontrib><creatorcontrib>Gandía, Jorge</creatorcontrib><creatorcontrib>Jiménez-Sabado, Verónica</creatorcontrib><creatorcontrib>Lozano-Velasco, Estefanía</creatorcontrib><creatorcontrib>Serra, Selma A</creatorcontrib><creatorcontrib>Vallmitjana, Alexander</creatorcontrib><creatorcontrib>Vázquez Ruiz de Castroviejo, Eduardo</creatorcontrib><creatorcontrib>Benítez, Raúl</creatorcontrib><creatorcontrib>Aranega, Amelia</creatorcontrib><creatorcontrib>Muñoz-Guijosa, Christian</creatorcontrib><creatorcontrib>Franco, Diego</creatorcontrib><creatorcontrib>Cinca, Juan</creatorcontrib><creatorcontrib>Hove-Madsen, Leif</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Recercat</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Herraiz-Martínez, Adela</au><au>Llach, Anna</au><au>Tarifa, Carmen</au><au>Gandía, Jorge</au><au>Jiménez-Sabado, Verónica</au><au>Lozano-Velasco, Estefanía</au><au>Serra, Selma A</au><au>Vallmitjana, Alexander</au><au>Vázquez Ruiz de Castroviejo, Eduardo</au><au>Benítez, Raúl</au><au>Aranega, Amelia</au><au>Muñoz-Guijosa, Christian</au><au>Franco, Diego</au><au>Cinca, Juan</au><au>Hove-Madsen, Leif</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2019-03-01</date><risdate>2019</risdate><volume>115</volume><issue>3</issue><spage>578</spage><epage>589</epage><pages>578-589</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><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.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>30219899</pmid><doi>10.1093/cvr/cvy215</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0008-6363 |
| ispartof | Cardiovascular research, 2019-03, Vol.115 (3), p.578-589 |
| issn | 0008-6363 1755-3245 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6383060 |
| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Recercat; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Action Potentials - genetics Aged Atrial Fibrillation - diagnosis Atrial Fibrillation - genetics Atrial Fibrillation - metabolism Atrial Fibrillation - physiopathology Calcium - metabolism Calcium Signaling - genetics Cardiologia Case-Control Studies Chromosomes, Human, Pair 4 Electrònica biomèdica Electrònica en cardiologia Enginyeria biomèdica Female Genetic Association Studies Genetic Predisposition to Disease Heart Atria - metabolism Heart Atria - physiopathology Heart Rate - genetics Homeostasis Human atrial myocytes Humans Informàtica Male Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Original Phenotype Phosphorylation Polymorphism, Single Nucleotide Risk Factors Ryanodine receptor Ryanodine Receptor Calcium Release Channel - metabolism Sarcoplasmic reticulum calcium release Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism Single nucleotide polymorphisms Spontaneous electrical activity Àrees temàtiques de la UPC |
| title | The 4q25 variant rs13143308T links risk of atrial fibrillation to defective calcium homoeostasis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T12%3A10%3A34IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%204q25%20variant%20rs13143308T%20links%20risk%20of%20atrial%20fibrillation%20to%20defective%20calcium%20homoeostasis&rft.jtitle=Cardiovascular%20research&rft.au=Herraiz-Mart%C3%ADnez,%20Adela&rft.date=2019-03-01&rft.volume=115&rft.issue=3&rft.spage=578&rft.epage=589&rft.pages=578-589&rft.issn=0008-6363&rft.eissn=1755-3245&rft_id=info:doi/10.1093/cvr/cvy215&rft_dat=%3Cproquest_pubme%3E2108248269%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2108248269&rft_id=info:pmid/30219899&rft_oup_id=10.1093/cvr/cvy215&rfr_iscdi=true |