The Role of Circulating Fatty Acids in Mediating the Effect of Insomnia on Heart Failure: A Two-Step, Two-Sample Mendelian Randomization Study

Bo Zuo,1,&ast; Binhe Yu,2,&ast; Pengwei Wang,2,3 Chong Zhang,1 Chenhao Zhao,2 Yujing Sun,2 Sizhi Ai2,4– 6 1Department of Cardiology, Cardiovascular Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Cardiology, Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui, People’s Republic of China; 3The Fourth Clinical College of Xinxiang Medical University, Xinxiang, People’s Republic of China; 4Center for Sleep and Circadian Medicine, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 5Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 6Institute of Psycho-Neuroscience, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Sizhi Ai, Department of Cardiology, Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, No. 88 Jiankang Road, Weihui, 453100, People’s Republic of China, Tel +0373-4402155, Email [email protected]: Previous studies support the causal effect of insomnia on heart failure. Fatty acid metabolism plays key roles in the occurrence and development of heart failure. It is unclear whether fatty acids play roles in the causal association between insomnia and heart failure. This study aims to investigate the mediating role of fatty acids in the association between insomnia and heart failure.Methods: We performed two-step, two-sample Mendelian randomization analysis by applying SNPs as genetic instruments for exposures, mediators and outcomes. Summary data obtained from genome-wide association studies for insomnia, proposed fatty acid mediators and heart failure were used in this study. The overall effect of insomnia on heart failure includes direct and indirect effects.Results: Genetically predicted insomnia has a significant causal effect on circulating total fatty acids, saturated fatty acids, monounsaturated fatty acids and omega-3 fatty acids. In addition, different circulating fatty acids have no causal effect on insomnia incidence. A significant positive correlation between genetic predicted insomnia and heart failure (OR = 1.10, 95% CI: 1.06– 1.14, P< 0.001) was observed. Finally, we found that circulating fatty acids play a mediating role in the causal association between insomnia and heart failure. Total fatty acids, saturated fatty acids and monounsaturated fatty acids explained 3% (95% CI: 0%-7.5%), 3% (95% CI: − 1.1%-7.5%), 4% (95% CI: 0%- 9.7%) of the overall effect of insomnia on heart failure, respectively.Conclusion: These results support circulating fatty acids as potential mediators in the causal association between insomnia and heart failure.Keywords: Mendelian randomization, insomnia, heart failure, circulating fatty acids