| Summary: | Chronic lack of sleep has been shown to be deleterious to our health. A variable number tandem repeat (VNTR) polymorphism in PERIOD3 (PER3) gene (rs57875989), has been reported to associate with diurnal preference, sleep propensity, vulnerability to sleep loss, and risk of cancer and mental illnesses. Although sleep loss at the molecular level in animal models has been studied extensively, there is a paucity of data in humans. The aim of the current study was to investigate the dependent and independent effects of the PER3 VNTR polymorphism and sleep loss on gene expression. Men and women homozygous for either the long (P ER35/5) or short (P ER34/4) P ER3 VNTR polymorphism underwent 7 sleep-wake cycles of either sleep restriction (SR) (6 h sleep) or sleep extension (SE) (10 h sleep) in a cross-over design, followed by 40-h constant routine (CR), during which time blood samples for assessing global gene expression were collected 3-hourly. Compared to SE, SR resulted in greater changes in expression in genes involved in neuronal plasticity, immune response, cellular stress response, energy metabolism, sleep-deprivation response, and clock genes in comparison to the effects of CR, suggesting that effects of chronic sleep loss result in more severe consequences than acute lack of sleep. Entrained timing of habitual sleep and wakefulness was shown to correlate with the timing of NRIDl (REV-ERBα), NRID2 (REV-ERBβ), BHLHE41 (DEC2), CSNKl D and TIMELESS expression, suggesting a prominent role for these genes in the regulation of sleep-wake behaviour. Additionally, REV-ERBα and REV- ERBf3 phase of expression showed correlations with sleep-wake timing in P ER34/4, but not in PER35/5. Additional genes identified as differentially expressed between the P ER3 homozygotes were involved m Immune function, phosphorylation/dephosphorylation, chronotype determination, and neurophysiology. A stably expressed reference gene, β-actin, for real-time PCR analysis of circadian time-series data in blood was also identified.
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