Genetic insight into sick sinus syndrome.
KRT8
Atrial fibrillation
GWAS
Mendelian randomization
Sick sinus syndrome
Journal
European heart journal
ISSN: 1522-9645
Titre abrégé: Eur Heart J
Pays: England
ID NLM: 8006263
Informations de publication
Date de publication:
21 05 2021
21 05 2021
Historique:
received:
28
04
2020
revised:
24
08
2020
accepted:
05
01
2021
pubmed:
14
2
2021
medline:
3
6
2021
entrez:
13
2
2021
Statut:
ppublish
Résumé
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. 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). 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.
Identifiants
pubmed: 33580673
pii: 6134552
doi: 10.1093/eurheartj/ehaa1108
pmc: PMC8140484
doi:
Substances chimiques
NAV1.8 Voltage-Gated Sodium Channel
0
SCN10A protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1959-1971Investigateurs
Steffen Andersen
(S)
Christian Erikstrup
(C)
Thomas F Hansen
(TF)
Henrik Hjalgrim
(H)
Gregor Jemec
(G)
Poul Jennum
(P)
Mette Nyegaard
(M)
Mie T Bruun
(MT)
Mikkel Petersen
(M)
Thomas Werge
(T)
Per I Johansson
(PI)
Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.
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