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A PERIOD3 variable number tandem repeat polymorphism modulates melatonin treatment response in delayed sleep-wake phase disorder.
Journal of Pineal Research ( IF 8.3 ) Pub Date : 2020-07-18 , DOI: 10.1111/jpi.12684
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 Kennaway 7 , Steven W Lockley 1, 2, 8, 9 , Leon C Lack 6 , Ronald R Grunstein 2, 4 , Simon N Archer 10 , Shantha M W Rajaratnam 1, 2, 8, 9 ,
Affiliation  

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 (PER34/4 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 PER34/4 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 PER34/4 individuals only. Melatonin did not advance circadian phase. Overall, PER34/4 DSWPD patients have a greater response to melatonin treatment. PER3 genotyping may therefore improve DSWPD patient outcomes.

中文翻译:

PERIOD3 可变数量串联重复多态性调节延迟睡眠 - 觉醒阶段障碍中的褪黑激素治疗反应。

我们检查了PERIOD3基因 ( PER3; rs57875989 )的多态性是否调节了褪黑激素在延迟睡眠 - 觉醒阶段障碍 (DSWPD) 中的睡眠促进作用。104 名 DSWPD 患者(53 名男性;29.4 ±10.0 岁)收集了口腔拭子用于基因分型(PER3 4/4 n = 43;PER35 等位基因 [杂合和纯合] n = 60)。参与者被随机分配到安慰剂或 0.5 毫克褪黑激素组,在所需的就寝时间前 1 小时(或 DLMO 前约 1.45 小时)服用,并在所需的就寝时间(4 周;每周 5-7 晚)尝试睡眠。我们评估了睡眠(日记和活动记录)、匹兹堡睡眠质量指数 (PSQI)、失眠严重程度指数 (ISI)、患者报告结果测量信息系统(PROMIS:睡眠障碍、睡眠相关障碍)、希恩残疾量表 (SDS) 和患者和临床医生的整体改进(PGI-C、CGI-C)。褪黑激素对活动性睡眠开始时间的治疗反应在基因型之间没有差异。对于PER3 4/4携带者,与接受安慰剂的患者相比,接受褪黑激素治疗的患者自我报告的入睡时间提前了更多,入睡潜伏期 (SOL) 更短 ( P  = .008),而前三分之一的活动图睡眠效率睡眠发作(SE T1)没有区别。对于PER3 5 载体,actigraphic SOL 和 SE T1 显示出使用褪黑激素有更大的改善 ( P  < .001)。褪黑激素改善 ISI ( P  = .005)、PROMIS 睡眠障碍 ( P  < .001) 和睡眠相关障碍 ( P  = .017)、 SDS ( P  = .019)、 PGI-C ( P  = .028) 和 CGI -C ( P  = .016) 在PER3 4/4仅限个人。褪黑激素没有提前昼夜节律阶段。总体而言,PER3 4/4 DSWPD 患者对褪黑激素治疗的反应更大。因此,PER3基因分型可能会改善 DSWPD 患者的预后。
更新日期:2020-07-18
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