DQB1*0602-positive subjects showed decreased sleep homeostatic pressure with differentially steeper declines, and greater sleepiness and fatigue during baseline. During PSD, positive subjects displayed SWE elevation comparable to negative subjects, despite higher sleepiness and fatigue. DQB1*0602-positive subjects also had more fragmented sleep during baseline and PSD and showed differentially greater REM sleep latency reductions and smaller stage 2 reductions, along with differentially greater increases in fatigue. Cumulative decreases in cognitive performance were comparable between groups during PSD. Thus, DQB1*0602 associated with interindividual differences in sleep homeostasis, physiologic sleep, sleepiness, and fatigue, but not cognitive responses, during baseline and PSD. DQB1*0602 may be a genetic marker for predicting such individual differences; moreover, its positivity in healthy subjects may represent a continuum with narcoleptic sleep–wake features.
Both groups showed greater physiologic sleepiness, sleep homeostasis, and self-rated sleepiness and fatigue, and poorer performance on the DS and PVT, across PSD. Thus, PSD produced substantial changes in these measures characteristic of cumulative sleep loss, thereby validating our phenotype.1,4,6,8,22–25
-positive subjects showed greater sleepiness and fatigue during baseline and PSD. Our results concur with a study that found that positive subjects with insomnia had poorer perceptions of sleep quality and degree of restfulness.26
Such symptoms may be part of a subclinical, but not pathologic continuum of daytime sleepiness (the most debilitating symptom of narcolepsy and a requirement for its diagnosis27
), and may have utility for predicting responses in DQB1*0602
carriers in work or operational settings.
Under basal, fully rested homeostatic pressure conditions, DQB1*0602
-positive subjects had lower SWE and SWA—putative markers of sleep homeostasis. By contrast, narcoleptic subjects have comparable or higher baseline SWA than controls.28–30
Our baseline differences were not sustained during PSD, indicating that positive subjects possess fully intact, efficient homeostatic responses to sleep loss. Equivalent responses have been reported in DQB1*0602
-positive narcoleptic subjects,28,29
and in another study, relatively greater SWA responses were observed in narcoleptic subjects than controls30
typing was not performed). Different genes may modulate basal vs evoked homeostatic responses in healthy sleepers; therefore, other genetic markers may influence differential vulnerability in SWA/SWE responses to PSD.
-positive subjects showed more fragmented sleep during baseline and PSD—as indicated by more nocturnal awakenings, WASO, and stage 2 sleep, and less SWS, but did not differ in TST or REM sleep latency or duration. Our findings concur with those demonstrating that DQB1*0602
-positive subjects with insomnia had more nighttime awakenings.26
-positive narcoleptic subjects showed more disrupted nighttime sleep (reduced SE, increased WASO, awakenings, and stage 1 sleep), less stage 2, shorter nocturnal REM sleep and SOL, more REM sleep, and more daytime objective sleepiness abnormalities (decreased SOL and increased number of sleep-onset REM sleep periods on the MWT and MSLT) than DQB1*0602
-negative narcoleptic subjects or controls.27,28,30–33 DQB1*0602
positivity may relate to common sleep changes such as disturbance of sleep maintenance mechanisms found in healthy subjects and narcoleptic subjects.
Our data contrast those from a study that found that DQB1*0602
-positive subjects showed shorter REM sleep latency and greater sleep continuity (e.g., better SE, decreased stage 1 sleep and WASO), and no differences in subjective or physiologic sleepiness measures (Stanford and Epworth Sleepiness Scales, MSLT).12
Study design differences might explain these contrasting results. While the aforementioned study employed a large sample (n = 525), because of its epidemiologic design, it did not utilize adaptation/saturation nights, and did not impose prestudy regularized sleep–wake cycles—factors which significantly affect PSG and sleepiness measures.12
Indeed, the reported REM sleep abnormalities12
may be eliminated when DQB1*0602
-positive subjects are well-rested during baseline (this study), and may be replaced by increased sleepiness and sleep fragmentation; as such, our results highlight the importance of insuring well-rested conditions in clinical PSG studies to eliminate possible effects on outcome measures. Further studies are needed to resolve these discrepancies.
Since narcolepsy associates with genes other than DQB1*0602
T-cell receptor α locus,21
and tumor necrosis factor–α,35
it is not surprising that DQB1*0602
-positive healthy subjects do not show all the same deficits—even to a lesser degree—than narcoleptic subjects. DQB1*0602
may be involved in common features shared between positive normal sleepers and narcoleptic subjects, whereas other genes may influence disparate features. Alternatively, sleep variables may be mediated by individuals' immune and infectious status, which may differ between positive and negative subjects. HLA alleles modulate susceptibility to many infectious and autoimmune diseases.36
does not mediate individual differences in cognitive performance. These findings sharply contrast sleep homeostatic, physiologic sleep, sleepiness, and fatigue differences, and concur with findings that homeostatic sleep responses to deprivation are not reflected in waking neurobehavioral or cognitive responses.1,6,37,38
Which genes mediate individual differences in cognitive performance during PSD remains unknown.
Despite our relatively large sample size compared to other genetic studies using sleep deprivation protocols,9,11,38,39
our results should be considered preliminary. As is true for the aforementioned studies, our findings should be replicated in a separate sample using an identical protocol—replication is critical for validation and avoiding false-positives in candidate gene studies.40
DQB1*0602—closely linked to the neurologic disorder narcolepsy—predicted interindividual differences in sleep homeostasis, physiologic sleep, and sleepiness and fatigue in healthy adults. DQB1*0602, therefore, may be a genetic marker for determining responses in the general population to basal conditions and chronic PSD—a condition associated with significant health consequences and experienced worldwide by millions of individuals frequently due to work and social obligations.