Genetic insight into sick sinus syndrome

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.

Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling

“…This could be explained by the relatively complex architecture of the channels encoded by SCN5A genes, i.e., Nav1.5, (four homodomains, characterized each by six transmembrane regions with voltage sensitivity (S1-S4) and pore modulation (S5 and S6) [153]), thus mutations occurring in several genetic points could induce protein loss-of-function. Apart for these proteins, other related to the cell electrical activity (e.g., KCNE2, ankyrin-B adapter, PITX2, titin, calcium voltage-gated channels) and nuclear envelope (lamin A/C) were found associated with SSS when in genetic variance or polymorphism [154][155][156][157][158].…”

Cohort profile: Copenhagen Hospital Biobank - Cardiovascular Disease Cohort (CHB-CVDC): Construction of a large-scale genetic cohort to facilitate a better understanding of heart diseases

“…42 43 A genome-wide association study of 6 469 sick sinus syndrome cases and more than a million controls revealed six loci associated to the disease. 44 Mendelian randomisation suggests a direct role of AF and lower heart rate in the development of sick sinus syndrome. 44 Angioedema is a known adverse drug reaction in individuals treated with antihypertensive ACE inhibitors.…”

“…44 Mendelian randomisation suggests a direct role of AF and lower heart rate in the development of sick sinus syndrome. 44 Angioedema is a known adverse drug reaction in individuals treated with antihypertensive ACE inhibitors. A Danish study has found common variants located close to the bradykinin receptor B 2 gene to be associated with increased risk of developing angioedema related to treatment with ACE inhibitors.…”

“… 44 Mendelian randomisation suggests a direct role of AF and lower heart rate in the development of sick sinus syndrome. 44 …”

Zfhx3 Transcription Factor Represses the Expression of SCN5A Gene and Decreases Sodium Current Density (INa)

“…Moreover, an update meta-analysis demonstrated that rs7193343 and rs2106261 were not associated with AF recurrence [ 11 ]. More recently, variants in ZFHX3 were also associated with sick sinus syndrome [ 12 ].…”