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Genetic insight into sick sinus syndrome

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dc.contributor Landspitali - The National University Hospital of Iceland
dc.contributor.author DBDS Genomic Consortium
dc.date.accessioned 2022-05-31T01:01:44Z
dc.date.available 2022-05-31T01:01:44Z
dc.date.issued 2021-02-13
dc.identifier.citation 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
dc.identifier.issn 0195-668X
dc.identifier.other PURE: 36961766
dc.identifier.other PURE UUID: dbf7594a-dffc-4c61-a84f-d6a6becc31d4
dc.identifier.other Scopus: 85107088568
dc.identifier.other unpaywall: 10.1093/eurheartj/ehaa1108
dc.identifier.uri https://hdl.handle.net/20.500.11815/3201
dc.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.
dc.description.abstract 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 in the development of SSS.
dc.format.extent 13
dc.format.extent 1959-1971
dc.language.iso en
dc.relation.ispartofseries European Heart Journal; 42(20)
dc.rights info:eu-repo/semantics/openAccess
dc.subject Gáttatif
dc.subject Sykursýki
dc.subject Sjúkur skiptahnútur
dc.subject Sjúkur skiptahnútur
dc.subject Atrial fibrillation
dc.subject GWAS
dc.subject KRT8
dc.subject Mendelian randomization
dc.subject Sick sinus syndrome
dc.subject Genome-Wide Association Study
dc.subject NAV1.8 Voltage-Gated Sodium Channel
dc.subject Sick Sinus Syndrome/genetics
dc.subject Humans
dc.subject Diabetes Mellitus, Type 2
dc.subject Atrial Fibrillation/genetics
dc.subject Pacemaker, Artificial
dc.subject Cardiology and Cardiovascular Medicine
dc.title Genetic insight into sick sinus syndrome
dc.type /dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article
dc.description.version Peer reviewed
dc.identifier.pmid 33580673
dc.identifier.doi https://doi.org/10.1093/eurheartj/ehaa1108
dc.relation.url http://www.scopus.com/inward/record.url?scp=85107088568&partnerID=8YFLogxK
dc.contributor.department Faculty of Medicine
dc.contributor.department Office of Division of Diagnostic and Support Services
dc.contributor.department Faculty of Industrial Engineering, Mechanical Engineering and Computer Science
dc.contributor.department Clinical Laboratory Services, Diagnostics and Blood Bank
dc.contributor.school Health Sciences

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