Genetic insight into sick sinus syndrome
Funding text This work was partly supported by NordForsk through the funding to PM Heart, project number 90580, the Innovation Fund Denmark (IFD) under File No. 8114-00033B and the Technology Development Fund, Iceland, project number 90580. © The Author(s) 2021. Published by Oxford University Press...
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ftopinvisindi:oai:opinvisindi.is:20.500.11815/3201 2023-11-12T04:19:35+01:00 Genetic insight into sick sinus syndrome DBDS Genomic Consortium Faculty of Medicine Office of Division of Diagnostic and Support Services Faculty of Industrial Engineering, Mechanical Engineering and Computer Science Clinical Laboratory Services, Diagnostics and Blood Bank Health Sciences Landspitali - The National University Hospital of Iceland 2021-02-13 13 2036997 1959-1971 https://hdl.handle.net/20.500.11815/3201 https://doi.org/10.1093/eurheartj/ehaa1108 en eng European Heart Journal; 42(20) http://www.scopus.com/inward/record.url?scp=85107088568&partnerID=8YFLogxK DBDS Genomic Consortium 2021 , ' Genetic insight into sick sinus syndrome ' , European Heart Journal , vol. 42 , no. 20 , pp. 1959-1971 . https://doi.org/10.1093/eurheartj/ehaa1108 0195-668X 36961766 dbf7594a-dffc-4c61-a84f-d6a6becc31d4 85107088568 33580673 unpaywall: 10.1093/eurheartj/ehaa1108 https://hdl.handle.net/20.500.11815/3201 doi:10.1093/eurheartj/ehaa1108 info:eu-repo/semantics/openAccess Gáttatif Sykursýki Sjúkur skiptahnútur Atrial fibrillation GWAS KRT8 Mendelian randomization Sick sinus syndrome Genome-Wide Association Study NAV1.8 Voltage-Gated Sodium Channel Sick Sinus Syndrome/genetics Humans Diabetes Mellitus Type 2 Atrial Fibrillation/genetics Pacemaker Artificial Cardiology and Cardiovascular Medicine /dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article 2021 ftopinvisindi https://doi.org/20.500.11815/320110.1093/eurheartj/ehaa1108 2023-11-01T23:55:20Z Funding text This work was partly supported by NordForsk through the funding to PM Heart, project number 90580, the Innovation Fund Denmark (IFD) under File No. 8114-00033B and the Technology Development Fund, Iceland, project number 90580. © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. Aims: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF ... Article in Journal/Newspaper Iceland Opin vísindi (Iceland) European Heart Journal 42 20 1959 1971 |
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Opin vísindi (Iceland) |
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language |
English |
topic |
Gáttatif Sykursýki Sjúkur skiptahnútur Atrial fibrillation GWAS KRT8 Mendelian randomization Sick sinus syndrome Genome-Wide Association Study NAV1.8 Voltage-Gated Sodium Channel Sick Sinus Syndrome/genetics Humans Diabetes Mellitus Type 2 Atrial Fibrillation/genetics Pacemaker Artificial Cardiology and Cardiovascular Medicine |
spellingShingle |
Gáttatif Sykursýki Sjúkur skiptahnútur Atrial fibrillation GWAS KRT8 Mendelian randomization Sick sinus syndrome Genome-Wide Association Study NAV1.8 Voltage-Gated Sodium Channel Sick Sinus Syndrome/genetics Humans Diabetes Mellitus Type 2 Atrial Fibrillation/genetics Pacemaker Artificial Cardiology and Cardiovascular Medicine DBDS Genomic Consortium Genetic insight into sick sinus syndrome |
topic_facet |
Gáttatif Sykursýki Sjúkur skiptahnútur Atrial fibrillation GWAS KRT8 Mendelian randomization Sick sinus syndrome Genome-Wide Association Study NAV1.8 Voltage-Gated Sodium Channel Sick Sinus Syndrome/genetics Humans Diabetes Mellitus Type 2 Atrial Fibrillation/genetics Pacemaker Artificial Cardiology and Cardiovascular Medicine |
description |
Funding text This work was partly supported by NordForsk through the funding to PM Heart, project number 90580, the Innovation Fund Denmark (IFD) under File No. 8114-00033B and the Technology Development Fund, Iceland, project number 90580. © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. Aims: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF ... |
author2 |
Faculty of Medicine Office of Division of Diagnostic and Support Services Faculty of Industrial Engineering, Mechanical Engineering and Computer Science Clinical Laboratory Services, Diagnostics and Blood Bank Health Sciences Landspitali - The National University Hospital of Iceland |
format |
Article in Journal/Newspaper |
author |
DBDS Genomic Consortium |
author_facet |
DBDS Genomic Consortium |
author_sort |
DBDS Genomic Consortium |
title |
Genetic insight into sick sinus syndrome |
title_short |
Genetic insight into sick sinus syndrome |
title_full |
Genetic insight into sick sinus syndrome |
title_fullStr |
Genetic insight into sick sinus syndrome |
title_full_unstemmed |
Genetic insight into sick sinus syndrome |
title_sort |
genetic insight into sick sinus syndrome |
publishDate |
2021 |
url |
https://hdl.handle.net/20.500.11815/3201 https://doi.org/10.1093/eurheartj/ehaa1108 |
genre |
Iceland |
genre_facet |
Iceland |
op_relation |
European Heart Journal; 42(20) http://www.scopus.com/inward/record.url?scp=85107088568&partnerID=8YFLogxK DBDS Genomic Consortium 2021 , ' Genetic insight into sick sinus syndrome ' , European Heart Journal , vol. 42 , no. 20 , pp. 1959-1971 . https://doi.org/10.1093/eurheartj/ehaa1108 0195-668X 36961766 dbf7594a-dffc-4c61-a84f-d6a6becc31d4 85107088568 33580673 unpaywall: 10.1093/eurheartj/ehaa1108 https://hdl.handle.net/20.500.11815/3201 doi:10.1093/eurheartj/ehaa1108 |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/20.500.11815/320110.1093/eurheartj/ehaa1108 |
container_title |
European Heart Journal |
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42 |
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20 |
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1959 |
op_container_end_page |
1971 |
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1782335973055528960 |