DQB1*0602 predicts interindividual differences in physiologic sleep, sleepiness, and fatigue

Abstract

Objective: The human leukocyte antigen (HLA) DQB1*0602 allele is closely associated with narcolepsy, a neurologic disorder characterized by excessive daytime sleepiness, fragmented sleep, and shortened REM sleep latency. We evaluated whether DQB1*0602 was a novel marker of interindividual differences by determining its relationship to sleep homeostatic, sleepiness, and cognitive responses to baseline and chronic partial sleep deprivation (PSD) conditions.

Methods: Ninety-two DQB1*0602-negative and 37 DQB1*0602-positive healthy adults participated in a protocol of 2 baseline 10 hours time in bed (TIB) nights followed by 5 consecutive 4 hours TIB nights. DQB1*0602 allelic frequencies did not differ significantly between Caucasians and African Americans.

Results: During baseline, although DQB1*0602-positive subjects were subjectively sleepier and more fatigued, they showed greater sleep fragmentation, and decreased sleep homeostatic pressure and differentially sharper declines during the night (measured by non-REM EEG slow-wave energy [SWE]). During PSD, DQB1*0602-positive subjects were sleepier and showed more fragmented sleep, despite SWE elevation comparable to negative subjects. Moreover, they showed differentially greater REM sleep latency reductions and smaller stage 2 reductions, along with differentially greater increases in fatigue. Both groups demonstrated comparable cumulative decreases in cognitive performance.

Conclusions: DQB1*0602 positivity in a healthy population may represent a continuum of some sleep-wake features of narcolepsy. DQB1*0602 was associated with interindividual differences in sleep homeostasis, physiologic sleep, sleepiness, and fatigue-but not in cognitive measures-during baseline and chronic PSD. Thus, DQB1*0602 may represent a genetic biomarker for predicting such individual differences in basal and sleep loss conditions.

Figure 1 Hourly slow-wave energy and slow-wave activity during baseline for the DQB1*0602 groups Mean (±SEM) hourly slow-wave energy (SWE) and slow-wave activity (SWA) derived from the C3 (A, B), Fz (C, D), or O2 (E, F) channels during baseline for DQB1*0602-negative subjects (open circles) and DQB1*0602-positive subjects (closed circles). SWE derived from C3 was lower in DQB1*0602-positive subjects (denoted by **, p < 0.05); SWA derived from C3 and SWE and SWA derived from the Fz channel showed similar trends. As expected, SWE and SWA showed a typical pattern of dissipation across the baseline night in all 3 channels for both groups (denoted by *, p < 0.05); moreover, DQB1*0602-positive subjects demonstrated sharper declines in sleep pressure derived from the O2 channel during the first few hours of the night than DQB1*0602-negative subjects (denoted by †, p < 0.05). In some records, EEG signal quality was insufficient or contained too much artifact for reliable power spectral analysis. Thus, the final sample sizes were as follows: for C3, DQB1*0602-negative (n = 68) and -positive (n = 24) subjects; for Fz, DQB1*0602-negative (n = 70) and -positive (n = 28) subjects; for O2, DQB1*0602-negative (n = 74) and -positive (n = 27) subjects.

Figure 2 Slow-wave energy and slow-wave activity during chronic partial sleep deprivation for the DQB1*0602 groups Mean (±SEM) hourly slow-wave energy (SWE) and slow-wave activity (SWA) as a percentage of baseline at the same corresponding hour derived from the C3 (A, B), Fz (C, D), or O2 (E, F) channels at partial sleep deprivation/restriction night 1 (SR1) and partial sleep deprivation/restriction night 5 (SR5) for hour 1 (H1) and hour 2 (H2) for DQB1*0602-negative subjects (open circles) and DQB1*0602-positive subjects (closed circles). SWE and SWA increased from SR1 to SR5 for the C3 and Fz channels (denoted by *, p < 0.05). There were no group differences or differential changes across nights. In some records, EEG signal quality was insufficient or contained too much artifact for reliable power spectral analysis. Thus, the final sample sizes were as follows: for SR1 and SR5 C3, DQB1*0602-negative (n = 72) and -positive (n = 28) subjects; for SR1 and SR5 Fz, DQB1*0602-negative (n = 72) and -positive (n = 27) subjects; for SR1 and SR5 O2, DQB1*0602-negative (n = 72) and -positive (n = 26) subjects.

Figure 3 Neurobehavioral performance during baseline and chronic partial sleep deprivation for the DQB1*0602 groups Mean (±SEM) scores per trial on the (A) Karolinska Sleepiness Scale (KSS), (B) “fresh-tired” visual analog scale (VAS), (C) Profile of Mood States (POMS)-Fatigue scale, and (D) Psychomotor Vigilance Task (PVT) lapses (>500 msec reaction times) per trial, (E) total number correct per trial on the Digit Symbol Substitution Task (DSST) and on the (F) Digit Span (DS) task, during baseline (B) and each partial sleep deprivation/restriction night (SR1–SR5) for DQB1*0602-negative subjects (open circles) and DQB1*0602-positive subjects (closed circles). Overall, DQB1*0602-positive subjects were more sleepy and fatigued as indicated by higher KSS, VAS, and POMS-Fatigue scores (denoted by **, p < 0.05). These scores all increased across chronic PSD (denoted by *, p < 0.05). Notably, the DQB1*0602-positive subjects also showed differentially larger increases in fatigue across chronic PSD than DQB1*0602-negative subjects (Panel C; denoted by †, p < 0.05). By contrast, although both groups showed increased PVT lapses (denoted by *, p < 0.05) and intersubject variability across chronic PSD, there were no differential responses in lapses nor did one group show more lapses at baseline or during chronic PSD. DSST scores failed to show significant changes across chronic PSD, or differential changes across days or group differences. DS total correct scores declined across chronic PSD (denoted by *, p < 0.05), but did not show significant group differences or differential changes.