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Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. (Uppsala University, Department of Neuroscience, Functional Pharmacology Unit)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. (Uppsala University, Department of Neuroscience, Functional Pharmacology Unit)ORCID iD: 0000-0002-6875-3928
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. (Uppsala University, Department of Neuroscience, Functional Pharmacology Unit)ORCID iD: 0000-0003-0000-7694
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. (Uppsala University, Department of Neuroscience, Functional Pharmacology Unit)ORCID iD: 0000-0001-6377-0270
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2021 (English)In: Frontiers in Bioscience-Landmark, Vol. 26, no 12, p. 1453-1463Article in journal (Refereed) Published
Abstract [en]

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). 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.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2021. Vol. 26, no 12, p. 1453-1463
Keywords [en]
insomnia; cronotype; statin treatment; genetic variants
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-439045DOI: 10.52586/5039ISI: 000742514300009OAI: oai:DiVA.org:uu-439045DiVA, id: diva2:1540577
Funder
Swedish Research CouncilAvailable from: 2021-03-29 Created: 2021-03-29 Last updated: 2024-04-03Bibliographically approved
In thesis
1. The role of HMG-coenzyme A reductase (HMGCR) and statin medication in the Central Nervous System: Cognitive Functions, Metabolism, Feeding and Sleep Behaviour
Open this publication in new window or tab >>The role of HMG-coenzyme A reductase (HMGCR) and statin medication in the Central Nervous System: Cognitive Functions, Metabolism, Feeding and Sleep Behaviour
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Millions of people are currently on statin medications (HMGCR inhibitors) to prevent cardiovascular diseases. Despite considerable central nervous system expression, little is known about HMGCR function in the brain. In Paper I, we used Drosophila and rodent models and found that inhibiting Hmgcr expression in the insulin-producing cells of the Drosophila hypothalamus equivalent, known as the pars intercerebralis (PI), throughout development, significantly reduces the expression of Insulin–like peptides 2 and 3 (ILP2 and ILP3), severely decreasing insulin signalling. This reduction causes decreased body size, hyperglycemia, increased lipid storage, and hyperphagia. We also discovered that Farnesyl pyrophosphate synthase (Fpps), an enzyme downstream of Hmgcr in the mevalonate pathway, is required for ILP2 expression in the PI. In rodents, acute inhibition of hypothalamic Hmgcr stimulates food intake as well. Furthermore, in rats, we found two regions within the hypothalamus that had significantly increased neural activity, the paraventricular nucleus and arcuate nucleus, which are known to regulate food intake. In Paper II, we explored the effects of statins on cognition and performed an observational study on a population-based sample from the UK Biobank. Cognitive performance in terms of reaction time, working memory and fluid intelligence was analysed at baseline and two follow-ups. Subjects were classified depending on age (up to 65 and over 65 years). The effect of statin use differed between the two age groups, with a beneficial effect on reaction time in older persons and fluid intelligence in both age groups, and a negative effect on working memory in younger subjects. In Paper III, we examined association of single nucleotide polymorphisms within the HMGCR gene, rs17238484 and rs12916, with self-reported insomnia symptoms. We found that statin users are associated with a higher risk for self-reported insomnia. The HMGCR genetic variants were also associated with self-reported insomnia, but in different manner. Carriers the rs12916-T risk allele had a protective effect from insomnia symptoms. No associations were found for either statin takers or carriers of these HGCMR risk alleles and late evening chronotype. The increased risk of insomnia noted with statins is partially explained by a mechanism that might be independent of HMGCR inhibition. In Paper IV, we discovered a novel role for Hmgcr in sleep regulation in Drosophila, where lacking of pan-neuronal Hmgcr expression causes sleep-promoting effects. We also found that loss of Hmgcr expression specifically in the PI insulin-producing cells, recapitulates the effect of pan-neuronal Hmgcr inhibition. Conversely, inhibiting Hmgcr in only six PI DH44 expressing neurons has the opposite effect on sleep, increasing sleep latency and decreasing sleep duration. This bi-functional property of Hmgcr in the fly brain underlies its importance in sleep regulation. Furthermore, loss of Hmgcr showed no effect on circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2021. p. 35
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1739
Keywords
Statin, cardiovascular disease, HMGCR, PCSK9, sleep, insomnia, circadian, Chronotype, feeding
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-439049 (URN)978-91-513-1177-7 (ISBN)
Public defence
2021-05-20, A2:208b, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2021-04-29 Created: 2021-03-29 Last updated: 2021-05-25
2. Unveiling the Mechanisms for Statin-Associated Sleep Problems and Myopathy: Statin Medication, Sleep Problems and Myopathy Mechanisms
Open this publication in new window or tab >>Unveiling the Mechanisms for Statin-Associated Sleep Problems and Myopathy: Statin Medication, Sleep Problems and Myopathy Mechanisms
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Statins (3-hydroxy-3-methylglutaryl-CoA reductase, HMGCR, inhibitors) comprise the gold standard for the management of hypercholesterolaemia and prevention of cardiovascular disease (CVDs). However, they are accompanied by potential adverse effects, notably muscle pain and sleep disturbance. These side effects can significantly impact patient adherence to statin therapy and thus increase the risk for CVDs. Despite extensive research, the underlying mechanisms of statin-associated myopathy and sleep disturbance are poorly understood. 

In Paper I, we conducted a cross-sectional cohort study to investigate the association between statin use and genetic variants for HMGCR with the risk for insomnia and chronotype using UK biobank cohort data. Statin use, insomnia and chronotype were assessed by a self-report touchscreen questionnaire. Statin treatment was associated with an increased risk of insomnia compared to controls, while genetic variants for HMGCR inhibition were associated with a reduced risk for insomnia. No association with late evening chronotype were observed with statin use or genetic variants for HMGCR. 

In Paper II, we employed Drosophila melanogaster to examine the effect of statins and the role of central inhibition of Hmgcr on sleep behaviour. Flies were treated with fluvastatin for five days and Hmgcr was knocked down in pan neurons and pars intercerebralis (PI), equivalent to the mammalian hypothalamus. Sleep patterns were recorded and analysed. Pan-neuronal- as well as PI inhibition of Hmgcr recapitulates fluvastatin-induced enhanced sleep latency and reduced sleep duration. 

In Paper III, we deciphered the underlying mechanisms for statin-induced myopathy using D. melanogaster. We found that fluvastatin treatment induced muscular damage, mitochondrial phenotypes, lowered locomotion, reduced climbing activity and was associated with lipotoxicity, impaired muscle differentiation and regeneration, and lowered expression of skeletal muscle chloride channels. Interestingly, selective inhibition of skeletal muscle chloride channels recapitulates fluvastatin-induced myofibrillar damage and lowered climbing activity, while selective Hmgcr inhibition in the skeletal muscles recapitulates fluvastatin-induced mitochondrial round-shape and reduced locomotion activity. 

In Paper IV, we explored the sequential events of myofibril damage and mitochondrial phenotypes associated with fluvastatin and examined whether inhibition of Hmgcr in the skeletal muscles recapitulates fluvastatin effects on mitochondrial respiratory parameters using D. melanogaster. Acute fluvastatin treatment was associated with reduced mitochondrial content and roundness of the mitochondria without noticeable myofibrillar damage. Intriguingly, chronic fluvastatin treatment was associated with stronger mitochondrial phenotypes along with severe myofibrillar damage, which suggests that mitochondrial phenotypes precede myofibrillar damage. Moreover, selective Hmgcr inhibition did not impact mitochondrial respiratory functions. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 38
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2047
National Category
Medical and Health Sciences Basic Medicine Clinical Medicine
Research subject
Pharmacoepidemiology; Biology with specialization in Molecular Biology; Genetics; Neuroscience; Pharmacology
Identifiers
urn:nbn:se:uu:diva-525998 (URN)978-91-513-2121-9 (ISBN)
Public defence
2024-06-05, room A1:111a, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Funder
The Swedish Brain FoundationSwedish Research Council, 2019-01066
Available from: 2024-05-08 Created: 2024-04-03 Last updated: 2024-06-03

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Alsehli, Ahmed M.Clemensson, Laura EmilyRukh, GullCiuculete, Diana-MariaTan, XiaoAl-Sabri, Mohamed H.Williams, Michael J.Benedict, ChristianSchiöth, Helgi B.
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