Causal Effect of Obstructive Sleep Apnea on Sick Sinus Syndrome: A Bidirectional Mendelian Randomization Study

Weixiang Chen,1,* Wanqian Pan,1,* Lin Ling,1,* Bin Jiang,1 Yuzhen Zhang,1 Xiong Su,2 Tingbo Jiang,1 Jia Lin1 1Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, Peoples Republic of China; 2Department of Biochemistry and Molecular Biology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, Peoples Republic of China*These authors contributed equally to this workCorrespondence: Jia Lin, Department of Cardiology, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou, Jiangsu, 215006, Peoples Republic of China, Email [email protected] Tingbo Jiang, Department of Cardiology, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou, Jiangsu, 215006, Peoples Republic of China, Email [email protected]: Despite previous research establishing a connection between OSA and an increased risk of Bradyarrhythmias, the specific causal link between obstructive sleep apnea (OSA) and sick sinus syndrome (SSS) remains unexplored. This study aims to investigate the potential causal relationship between OSA and the development of SSS.Methods: To evaluate the association between OSA and SSS, we utilized a bidirectional two-sample Mendelian randomization (MR) method. Genetic variant OSA association data were sourced from FinnGens genome-wide association studies, comprising 410,385 individuals, while SSS association data were obtained from deCODE genetics, involving a dataset of 1, 000,187 individuals. Effect estimates were computed through the utilization of inverse-variance weighting (IVW), MR-Egger, weighted median, maximum likelihood techniques, and sensitivity analyses were conducted using the Mendelian Randomization Pleiotropy Residual Sum and Outlier (MR-PRESSO) approaches.Results: Our MR analyses utilizing IVW (fixed effects) revealed a heightened susceptibility to SSS among individuals with genetically predisposed OSA (OR= 1.493; 95% CI, 1.120– 1.990; P= 0.006), utilizing a set of 7 single nucleotide polymorphisms as the instrumental variables. MR-Egger analysis indicated an absence of evidence for genetic pleiotropy, as reflected by the intercept value of − 0.002 (SE 0.030, P= 0.930; global P= 0.719), but genetically predicted SSS did not causally contribute to OSA (OR= 0.997, 95% CI: 0.926– 1.072, P= 0.930).Conclusions: This MR analysis suggests a causal link between genetically predicted OSA and increased SSS risk. While finding no evidence for a causal relationship where SSS influences OSA. Keywords: sick sinus syndrome, obstructive sleep apnea, causal association, Mendelian randomization