Genetic insight into sick sinus syndrome-Reference-Cited by-同舟云学术

Genetic insight into sick sinus syndrome

Published:2021-02-13 Issue:20 Volume:42 Page:1959-1971
ISSN:0195-668X
Container-title:European Heart Journal
language:en
Short-container-title:

Author:

Thorolfsdottir Rosa B¹^ORCID,Sveinbjornsson Gardar¹^ORCID,Aegisdottir Hildur M¹,Benonisdottir Stefania¹^ORCID,Stefansdottir Lilja¹,Ivarsdottir Erna V¹^ORCID,Halldorsson Gisli H¹^ORCID,Sigurdsson Jon K¹,Torp-Pedersen Christian²^ORCID,Weeke Peter E³,Brunak Søren⁴,Westergaard David⁴^ORCID,Pedersen Ole B⁵^ORCID,Sorensen Erik⁶,Nielsen Kaspar R⁷^ORCID,Burgdorf Kristoffer S⁶^ORCID,Banasik Karina⁴^ORCID,Brumpton Ben⁸^ORCID,Zhou Wei⁹^ORCID,Oddsson Asmundur¹^ORCID,Tragante Vinicius¹^ORCID,Hjorleifsson Kristjan E¹¹⁰^ORCID,Davidsson Olafur B¹,Rajamani Sridharan¹,Jonsson Stefan¹,Torfason Bjarni¹¹¹²,Valgardsson Atli S¹²,Thorgeirsson Gudmundur¹¹¹¹³,Frigge Michael L¹,Thorleifsson Gudmar¹^ORCID,Norddahl Gudmundur L¹,Helgadottir Anna¹,Gretarsdottir Solveig¹,Sulem Patrick¹^ORCID,Jonsdottir Ingileif¹¹¹¹⁴^ORCID,Willer Cristen J⁹¹⁵¹⁶^ORCID,Hveem Kristian¹⁷¹⁸¹⁹,Bundgaard Henning³,Ullum Henrik⁶²⁰^ORCID,Arnar David O¹¹¹¹³,Thorsteinsdottir Unnur¹¹¹^ORCID,Gudbjartsson Daniel F¹²¹^ORCID,Holm Hilma¹^ORCID,Stefansson Kari¹¹¹^ORCID,Andersen Steffen,Erikstrup Christian,Hansen Thomas F,Hjalgrim Henrik,Jemec Gregor,Jennum Poul,Nyegaard Mette,Bruun Mie T,Petersen Mikkel,Werge Thomas,Johansson Per I,

Affiliation:

1. deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 101, Iceland

2. Department of Clinical Research and Cardiology, Nordsjaelland Hospital, Dyrehavevej 29, Hillerød 3400, Denmark

3. Department of Cardiology, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen 2100, Denmark

4. Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3A, Copenhagen 2200, Denmark

5. Department of Clinical Immunology, Naestved Hospital, Ringstedgade 77B, Naestved 4700, Denmark

6. Department of Clinical Immunology, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen 2100, Denmark

7. Department of Clinical Immunology, Aalborg University Hospital North, Urbansgade 36, Aalborg 9000, Denmark

8. Department of Thoracic and Occupational Medicine, St. Olavs Hospital, Trondheim University Hospital, Prinsesse Kristinas gate 3, Trondheim 7030, Norway

9. Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, MI 48109-2218, USA

10. Department of Computing and Mathematical Sciences, California Institute of Technology, 1200 E California Blvd. MC 305-16, Pasadena, CA 91125, USA

11. Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik 101, Iceland

12. Department of Cardiothoracic Surgery, Landspitali—The National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland

13. Department of Medicine, Landspitali—The National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland

14. Department of Immunology, Landspitali—The National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland

15. Department of Internal Medicine: Cardiology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109 -5368, USA

16. Department of Human Genetics, University of Michigan, 4909 Buhl Building, 1241 E. Catherine St., Ann Arbor, MI 48109 -5618, USA

17. K.G. Jebsen Center for Genetic Epidemiology, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Erling Skjalgssons gt. 1, Trondheim 7491, Norway

18. Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Postboks 8905, Trondheim 7491, Norway

19. HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Forskningsveien 2, Levanger 7600, Norway

20. Statens Serum Institut, Artillerivej 5, Copenhagen 2300, Denmark

21. School of Engineering and Natural Sciences, University of Iceland, Hjardarhagi 4, Reykjavik 107, Iceland

Abstract

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.

Funder

NordForsk

Innovation Fund Denmark

Technology Development Fund

Novo Nordisk Foundation

Publisher

Oxford University Press (OUP)

Subject

Cardiology and Cardiovascular Medicine

Link

http://academic.oup.com/eurheartj/article-pdf/42/20/1959/38103494/ehaa1108.pdf

Reference101 articles.