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Genetic insight into sick sinus syndrome

2021; Oxford University Press; Volume: 42; Issue: 20 Linguagem: Inglês

10.1093/eurheartj/ehaa1108

1522-9645

Rósa B. Þórólfsdóttir, Garðar Sveinbjörnsson, Hildur M. Aegisdottir, Stefania Benónísdóttir, Lilja Stefánsdóttir, Erna V. Ivarsdottir, Gísli H. Halldórsson, Jon K. Sigurdsson, Christian Torp‐Pedersen, Peter Weeke, Søren Brunak, David Westergaard, Ole Birger Pedersen, Erik Sørensen, Kaspar René Nielsen, Kristoffer Sølvsten Burgdorf, Karina Banasik, Ben Brumpton, Wei Zhou, Ásmundur Oddsson, Vinicius Tragante, Kristján Eldjárn Hjörleifsson, Olafur B. Davidsson, Sridharan Rajamani, Stefan Jonsson, Bjarni Torfason, Atli S. Valgardsson, Guðmundur Þorgeirsson, Michael L. Frigge, Guðmar Þorleifsson, Gudmundur L. Norddahl, Anna Helgadóttir, Sólveig Grétarsdóttir, Patrick Sulem, Ingileif Jónsdóttir, Cristen J. Willer, Kristian Hveem, Henning Bundgaard, Henrik Ullum, Davíð O. Arnar, Unnur Þorsteinsdóttir, Daníel F. Guðbjartsson, Hilma Hólm, Kári Stéfansson, Steffen Andersen, Christian Erikstrup, Thomas Hansen, Henrik Hjalgrim, Gregor B. E. Jemec, Poul Jennum, Mette Nyegaard, Mie Topholm Bruun, Mikkel Steen Petersen, Thomas Werge, Pär I. Johansson,

Biochemical Analysis and Sensing Techniques

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.