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Genetic insight into sick sinus syndrome.

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Authors
Thorolfsdottir, Rosa B
Sveinbjornsson, Gardar
Aegisdottir, Hildur M
Benonisdottir, Stefania
Stefansdottir, Lilja
Ivarsdottir, Erna V
Halldorsson, Gisli H
Sigurdsson, Jon K
Torp-Pedersen, Christian
Weeke, Peter E
Brunak, Søren
Westergaard, David
Pedersen, Ole B
Sorensen, Erik
Nielsen, Kaspar R
Burgdorf, Kristoffer S
Banasik, Karina
Brumpton, Ben
Zhou, Wei
Oddsson, Asmundur
Tragante, Vinicius
Hjorleifsson, Kristjan E
Davidsson, Olafur B
Rajamani, Sridharan
Jonsson, Stefan
Torfason, Bjarni
Valgardsson, Atli S
Thorgeirsson, Gudmundur
Frigge, Michael L
Thorleifsson, Gudmar
Norddahl, Gudmundur L
Helgadottir, Anna
Gretarsdottir, Solveig
Sulem, Patrick
Jonsdottir, Ingileif
Willer, Cristen J
Hveem, Kristian
Bundgaard, Henning
Ullum, Henrik
Arnar, David O
Thorsteinsdottir, Unnur
Gudbjartsson, Daniel F
Holm, Hilma
Stefansson, Kari
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Issue Date
2021-05

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Citation
Thorolfsdottir RB, Sveinbjornsson G, Aegisdottir HM, Benonisdottir S, Stefansdottir L, Ivarsdottir EV, Halldorsson GH, Sigurdsson JK, Torp-Pedersen C, Weeke PE, Brunak S, Westergaard D, Pedersen OB, Sorensen E, Nielsen KR, Burgdorf KS, Banasik K, Brumpton B, Zhou W, Oddsson A, Tragante V, Hjorleifsson KE, Davidsson OB, Rajamani S, Jonsson S, Torfason B, Valgardsson AS, Thorgeirsson G, Frigge ML, Thorleifsson G, Norddahl GL, Helgadottir A, Gretarsdottir S, Sulem P, Jonsdottir I, Willer CJ, Hveem K, Bundgaard H, Ullum H, Arnar DO, Thorsteinsdottir U, Gudbjartsson DF, Holm H, Stefansson K; DBDS Genomic Consortium. Genetic insight into sick sinus syndrome. Eur Heart J. 2021 May 21;42(20):1959-1971. doi: 10.1093/eurheartj/ehaa1108.
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. Keywords: KRT8; Atrial fibrillation; GWAS; Mendelian randomization; Sick sinus syndrome.
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Additional Links
https://academic.oup.com/eurheartj/article/42/20/1959/6134552
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140484/
Rights
© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.
ae974a485f413a2113503eed53cd6c53
10.1093/eurheartj/ehaa1108
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English Journal Articles (Peer Reviewed)

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