PER3 polymorphism and cardiac autonomic control: effects of sleep debt and circadian phase

Abstract

Viola AU, James LM, Archer SN, Dijk DJ. PER3 polymorphism and cardiac autonomic control: effects of sleep debt and circadian phase. Am J Physiol Heart Circ Physiol 295: H2156 -H2163, 2008; doi:10.1152/ajpheart.00662.2008.-A variable number tandem repeat polymorphism in the coding region of the circadian clock PERIOD3 (PER3) gene has been shown to affect sleep. Because circadian rhythms and sleep are known to modulate sympathovagal balance, we investigated whether homozygosity for this PER3 polymorphism is associated with changes in autonomic nervous system (ANS) activity during sleep and wakefulness at baseline and after sleep deprivation. Twenty-two healthy participants were selected according to their PER3 genotype. ANS activity, evaluated by heart rate (HR) and HR variability (HRV) indexes, was quantified during baseline sleep, a 40-h period of wakefulness, and recovery sleep. Sleep deprivation induced an increase in slow-wave sleep (SWS), a decrease in the global variability, and an unbalance of the ANS with a loss of parasympathetic predominance and an increase in sympathetic activity. Individuals homozygous for the longer allele (PER3 5/5 ) had more SWS, an elevated sympathetic predominance, and a reduction of parasympathetic activity compared with PER3 4/4 , in particular during baseline sleep. The effects of genotype were strongest during nonrapid eye movement (NREM) sleep and absent or much smaller during REM sleep. The NREM-REM cycle-dependent modulation of the low frequency-to-(low frequency ϩ high frequency) ratio was diminished in PER3 5/5 individuals. Circadian phase modulated HR and HRV, but no interaction with genotype was observed. In conclusion, the PER3 polymorphism affects the sympathovagal balance in cardiac control in NREM sleep similar to the effect of sleep deprivation. clock gene; autonomic nervous system; cardiovascular risk; slow wave activity GENETIC FACTORS have been identified as playing an important role in many physiological processes, especially those involved in cardiovascular control (5,10,34,46,57). Heart rate (HR) variability (HRV), defined as the variation in the interval between consecutive heart beats, is modulated by the autonomic nervous system and is an indicator of clinically relevant cardiovascular phenotypes. Reduced HRV is an independent predictor of cardiac disease and cardiac mortality (3,14,15,23,27,33,40,51). The primary explanation for this predictive effect is that reduced HRV reflects a shift in the cardiac sympathovagal balance from parasympathetic to sympathetic control over the autonomic nervous system (35, 45). Vigilance state and endogenous circadian phase are major modulators of the autonomic nervous system. Sympathetic activity is higher during wakefulness than sleep, and, within sleep, the sympathetic contribution is greater in rapid eye movement (REM) sleep than in deep non-REM (NREM) sleep (7, 56). During continuous wakefulness under controlled behavioural conditions, HRV is not constant but varies with circadian phase such that global HRV is great...

Diversity of Human Clock Genotypes and Consequences

“…Accompanying increased slow-wave sleep in subjects homozygous for the long allele is an elevated sympathetic predominance and a reduction of parasympathetic predominance in the autonomic nervous system. 97 Both homozygosity for the long allele and a SNP in exon 18, 1148 Arg, are associated with reduced daytime sleepiness, and also sleepiness in nurses working during shifts. 61,98 On the other hand, homozygosity of the 4-repeat allele correlates with insomnia in alcohol-dependent patients.…”

Per3 VNTR polymorphism and chronic heart failure

“…The connection between both could be viewed from the perspective of the possible effect of sleep deprivation on cardiac autonomic control, associating homozygozity in Per3 VNTR with heart rate (HR) and heart rate variability (HRV) (ref. 20 ). Although no interaction of HR and HRV with VNTR Per3 genotype was found, this polymorphism has been considered a potential marker for individual differences in the autonomic nervous system.…”

“…Among the most surveyed Per3 polymorphisms in the last five years is the biallelic length change near the putative phosphorylation site of exon 18, composed of 4 or 5 indirect repeats. Numerous studies have linked this VNTR polymorphism to overall control of autonomic balance during sleep and wake cycles and indirectly to cardiac autonomic control [18][19][20] . However, little is known about the exact clock mechanism in cardiovascular biology, and circadian rhythms in the heart have not yet been characterized at the transcriptional level, although several studies have shown that clock genes have an important function in myocardial contractile function and metabolism.…”

Chronobiology: Influences on Metabolic Syndrome and Cardiovascular Risk

“…Period genes such as PER3 polymorphism have also been associated with chronodisruption. It has been demonstrated that PER3 affects the sympathovagal balance of cardiac control in sleep similar to the effect of sleep deprivation [40].…”