Open Access

Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia

Ahmed M. Alsehli1,2,Gull Rukh2,*, Laura E. Clemensson2,Diana-Maria Ciuculete2,Xiao Tan2,Mohamed H. Al-Sabri2, Michael J. Williams2,Christian Benedict2,Helgi B. Schiöth2,3
Faculty of Medicine, King Abdulaziz University and Hospital, 21589 Jeddah, Kingdom of Saudi Arabia
Department of Neuroscience, Functional Pharmacology Unit, Uppsala Biomedical Centre (BMC), Uppsala University, 75124 Uppsala, Sweden
Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia
DOI: 10.52586/5039 Volume 26 Issue 12, pp.1453-1463
Submited: 04 August 2021 Revised: 14 October 2021
Accepted: 20 October 2021 Published: 30 December 2021
*Corresponding Author(s):  
Gull Rukh
Copyright: © 2021 The author(s). Published by BRI. This is an open access article under the CC BY 4.0 license (

Importance: Statins have been linked to an increased risk for insomnia, but the literature is controversial. Moreover, it is unknown, if the potential effects are directly related to the inhibition of the statin target HMGCR, the subsequently lowered cholesterol levels, or other off-target effects of statins. Aims: To investigate the association of statin treatment and genetic proxies of cholesterol lowering drugs with the risk for insomnia and chronotype in a large population-based cohort. Methods: A cross-sectional cohort study based on baseline data collected between 2006–2010 in UK biobank cohort was conducted. European participants without any history of psychiatric/neurological disorders or of stroke and with available genetic data as well as information on statin use were included in the present study. Self-reported measures of insomnia and chronotype were analysed (a) in statin users versus control subjects, (b) subjects carrying single nucleotide polymorphisms (SNPs) in the HMGCR gene, which are associated with reduced enzymatic function and lower cholesterol levels (rs17238484 and rs12916) and (c) subjects carrying a SNP in the PCSK9 gene (rs1159147), which leads to lower cholesterol levels independent of HMGCR. The main analysis were performed using multivariable regression models. Statin treatment and SNPs in HMGCR and PCSK9 genes were used as exposures and main outcomes were insomnia and chronotype. Results: A total of 206,801participants (mean [SD] age, 57.5 [7.9] years; 56% women; 20% statin users) were included in the present study. Statin users had an increased risk of insomnia compared to controls (odds ratio [95% CI], 1.07 [1.03 to 1.11]; p = 1.42 ×× 10−4-4). A similar effect was observed for PCSK9 rs11591147-T allele (1.07 [1.01–1.14]; 0.014), while the two gene variants of HMGCR were associated with a reduced risk for insomnia (rs17238484-G: 0.97 [0.95 to 0.99]; 0.014 and rs12916-T: 0.97 [0.96 to 0.99]; 0.002). In regard to chronotype, there was no effect of either statin treatment or HMGCR SNPs, but the PCSK9 rs11591147-T allele was associated with a higher evening preference (1.17 [1.06 to 1.29]; 0.001). Conclusion: Our data suggests that statin treatment can pose an increased risk for insomnia in in the European population. Interestingly, there was no agreement between the effects of statins and the effects of reduced HMGCR activity based on genetic variants, suggesting that the observed unfavourable effect of statins on sleep is conveyed through other targets. This further explains why the literature on statin effects on sleep is not conclusive. Finally our data encourage further investigations into the molecular processes linking statins, HMGCR and PCSK9 to sleep behaviour.

Key words

Statin treatment; Genetic variants; Insomnia; Chronotype; Cholesterol-lowering drugs


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Ahmed M. Alsehli, Gull Rukh, Laura E. Clemensson, Diana-Maria Ciuculete, Xiao Tan, Mohamed H. Al-Sabri, Michael J. Williams, Christian Benedict, Helgi B. Schiöth. Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia. Frontiers in Bioscience-Landmark. 2021. 26(12); 1453-1463.