Zeping Xu,1,* Mingwei Ma,2,* Yanlong Liu,2,* Jiayi Tang,3 Xingguang Luo,4 Yu-Hsin Chen,2 Kexin Wang,2 Xiyi Chen,2 Yimin Kang,5 Ke Zheng,6 Weiming Hu,7 Li Chen,2 Fan Wang,8 Yuyu Wu9,10 

1Department of Pharmacy, Ningbo Medical Center Li Huili Hospital, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang, 315040, People’s Republic of China; 2School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Cixi Biomedical Research Institute, Wenzhou Medical University, Ningbo, People’s Republic of China; 4Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; 5Psychosomatic Medicine Research Division, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, People’s Republic of China; 6Department of Geriatrics, Wenzhou Seventh People’s Hospital, Wenzhou, Zhejiang Province, People’s Republic of China; 7Department of Psychiatry, The Third Hospital of Quzhou, Quzhou, People’s Republic of China; 8Beijing Huilongguan Hospital, Peking University, Beijing, Beijing Municipality, People’s Republic of China; 9Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, People’s Republic of China; 10School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Fan Wang; Yuyu Wu, Email fanwang@bjmu.edu.cn; douzipo@163.com

Objective: This study investigates the influence of CSF relaxin (RLN) on the association between smoking and sleep quality, considering previous findings linking smoking and RLN with psychiatric conditions.
Methods: In a case-control study of 168 Chinese adult males (70 smokers, 98 non-smokers), levels of relaxin in cerebrospinal fluid (CSF) were measured. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), comprising seven scales. Logistic regression and mediation models analyzed the relationships between nicotine dependence, PSQI scores, and CSF relaxin. Logistic regression examined the interaction of nicotine dependence and relaxin gene on PSQI subdimension scores.
Results: Smokers exhibited more severe sleep problems in PSQI total score and four PSQI subdimension scores (p < 0.05). CSF relaxin levels were significantly higher in smokers (20.7 ± 7.0 vs 16.3 ± 6.5, p < 0.001) and correlated closely with PSQI total score (r = 0.275, p < 0.001). Logistic regression found that CSF relaxin associated with PSQI subdimension scores, particularly in sleep disturbance (OR = 3.07 (1.61– 5.99), adjusted p < 0.01). Mediation analysis indicated relationship between nicotine dependence and PSQI total score, with CSF relaxin as a mediator, and the indirect effect accounted for 25% of the total effect (Indirect effect = 0.124 (0.021– 0.223), Total effect = 0.494 (0.193– 0.807)). Additionally, polymorphisms in gene of relaxin and its receptors were closely tied to smoking behaviors and sleep quality (p < 0.05).
Conclusion: CSF relaxin levels were significantly elevated in smokers and closely associated with PSQI subdimension scores, particularly with the sleep disturbance subdimension score. Moreover, CSF relaxin mediated the relationship between nicotine dependence and sleep quality. Polymorphisms (RLN3 rs12327666, rs1982632, and rs7249702, RLN3R1 rs35399, and RLN3R2 rs11264422) also played a role in smoking behaviors or sleep quality.

Keywords: smoking, PSQI score, relaxin, psychiatric disorders, mediation effect