A PERIOD3 variable number tandem repeat polymorphism modulates melatonin treatment response in delayed sleep‐wake phase disorder

Jul 19, 2020Journal of pineal research

A common genetic variation in the PERIOD3 gene influences how people with delayed sleep-wake phase disorder respond to melatonin treatment

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Abstract

One hundred and four individuals with Delayed Sleep-Wake Phase Disorder (DSWPD) were studied to assess the effects of melatonin based on their PERIOD3 gene polymorphism.

Melatonin treatment did not significantly change sleep onset time as measured by actigraphy across different genotypes.
For carriers of the PER3 polymorphism, self-reported sleep onset time was advanced and sleep onset latency was shorter with melatonin compared to placebo.
Actigraphic measures showed larger improvements in sleep onset latency and sleep efficiency for PER3 5 carriers after melatonin treatment.
Melatonin significantly improved self-reported insomnia severity, sleep disturbance, and sleep-related impairment in individuals with the PER3 genotype.
Melatonin did not advance circadian phase for any participants, suggesting its primary role in improving sleep quality rather than altering timing.

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We examined whether a polymorphism of the PERIOD3 gene (PER3; rs57875989) modulated the sleep-promoting effects of melatonin in Delayed Sleep-Wake Phase Disorder (DSWPD). One hundred and four individuals (53 males; 29.4 ±10.0 years) with DSWPD and a delayed dim light melatonin onset (DLMO) collected buccal swabs for genotyping (PER3n = 43; PER3 5 allele [heterozygous and homozygous] n = 60). Participants were randomised to placebo or 0.5 mg melatonin taken 1 hour before desired bedtime (or ~1.45 hours before DLMO), with sleep attempted at desired bedtime (4 weeks; 5-7 nights/week). We assessed sleep (diary and actigraphy), Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Patient-Reported Outcomes Measurement Information System (PROMIS: Sleep Disturbance, Sleep-Related Impairment), Sheehan Disability Scale (SDS) and Patient- and Clinician-Global Improvement (PGI-C, CGI-C). Melatonin treatment response on actigraphic sleep onset time did not differ between genotypes. For PER3carriers, self-reported sleep onset time was advanced by a larger amount and sleep onset latency (SOL) was shorter in melatonin-treated patients compared to those receiving placebo (P = .008), while actigraphic sleep efficiency in the first third of the sleep episode (SE T1) did not differ. For PER3 5 carriers, actigraphic SOL and SE T1 showed a larger improvement with melatonin (P < .001). Melatonin improved ISI (P = .005), PROMIS sleep disturbance (P < .001) and sleep-related impairment (P = .017), SDS (P = .019), PGI-C (P = .028) and CGI-C (P = .016) in PER3individuals only. Melatonin did not advance circadian phase. Overall, PER3DSWPD patients have a greater response to melatonin treatment. PER3 genotyping may therefore improve DSWPD patient outcomes. 4/4 4/4 4/4 4/4

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A PERIOD3 variable number tandem repeat polymorphism modulates melatonin treatment response in delayed sleep‐wake phase disorder

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