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

Michelle Magee; Tracey L Sletten; Jade M Murray; Christopher J Gordon; Nicole Lovato; Delwyn J Bartlett; David J Kennaway; Steven W Lockley; Leon C Lack; Ronald R Grunstein; Simon N Archer; Shantha M W Rajaratnam; Delayed Sleep on Melatonin (DelSoM) Study Group

doi:10.1111/jpi.12684

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

J Pineal Res. 2020 Nov;69(4):e12684. doi: 10.1111/jpi.12684. Epub 2020 Sep 16.

Authors

Michelle Magee^{1

2

3}, Tracey L Sletten^{1

2}, Jade M Murray^{1

2}, Christopher J Gordon^{2

4

5}, Nicole Lovato^{2

6}, Delwyn J Bartlett^{2

4}, David J Kennaway⁷, Steven W Lockley^{1

2

8

9}, Leon C Lack⁶, Ronald R Grunstein^{2

4}, Simon N Archer¹⁰, Shantha M W Rajaratnam^{1

2

8

9}; Delayed Sleep on Melatonin (DelSoM) Study Group

Affiliations

¹ Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, Victoria, Australia.
² Cooperative Research Centre for Alertness, Safety and Productivity, Clayton, Victoria, Australia.
³ Centre for Neuroscience of Speech, Department of Audiology and Speech Pathology, University of Melbourne, Parkville, Victoria, Australia.
⁴ Woolcock Institute of Medical Research, Sydney, NSW, Australia.
⁵ Sydney Nursing School, The University of Sydney, Sydney, NSW, Australia.
⁶ Adelaide Institute for Sleep Health: A Flinders Centre of Research Excellence, School of Medicine, Flinders University, Adelaide, South Australia, Australia.
⁷ Robinson Research Institute, Adelaide School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
⁸ Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA.
⁹ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
¹⁰ Surrey Sleep Research Centre, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.

PMID: 32682347
DOI: 10.1111/jpi.12684

Abstract

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 (PER3^4/4 n = 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 PER3^4/4 carriers, 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 PER3^4/4 individuals only. Melatonin did not advance circadian phase. Overall, PER3^4/4 DSWPD patients have a greater response to melatonin treatment. PER3 genotyping may therefore improve DSWPD patient outcomes.

Keywords: Delayed Sleep-Wake Phase Disorder; PERIOD3; circadian rhythm sleep disorders; melatonin; polymorphism; variable number tandem repeat.

Publication types

Multicenter Study
Randomized Controlled Trial

MeSH terms

Adult
Double-Blind Method
Female
Humans
Male
Melatonin / administration & dosage*
Period Circadian Proteins / genetics*
Polymorphism, Genetic*
Sleep Wake Disorders* / drug therapy
Sleep Wake Disorders* / genetics
Tandem Repeat Sequences*

Substances

PER3 protein, human
Period Circadian Proteins
Melatonin

Grants and funding

1031513/National Health and Medical Research Council