Genetic and clinical factors predict lithium's effects on PER2 gene expression rhythms in cells from bipolar disorder patients.
Genetic and clinical factors predict lithium's effects on PER2 gene expression rhythms in cells from bipolar disorder patients.
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遗传和临床因素可以预测锂对躁郁症患者细胞中PER2基因表达节律的影响。
DOI：
10.1038/tp.2013.90
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发表时间：
2013-10-22
影响因子：
6.8
通讯作者：
Welsh DK
中科院分区：
文献类型：
--
作者：
McCarthy MJ;Wei H;Marnoy Z;Darvish RM;McPhie DL;Cohen BM;Welsh DK
双相情感障碍（BD）与异常的昼夜节律有关。在对治疗有反应的BD患者中，锂（Li）可稳定情绪并降低自杀风险。锂还影响昼夜节律和控制它们的“时钟基因”的表达。然而，在何种程度上BD，李和昼夜节律钟共享共同的生物学机制是未知的，并已从BD患者的样本中的时钟基因功能的直接测量很少。因此，生物钟基因在BD和Li治疗中的作用仍不清楚。将来自BD患者（N=19）或健康对照（N=19）的皮肤成纤维细胞用Per2：：luc（节律表达的生物发光昼夜节律钟报告基因）转导，并连续5天测量节律。比较BD患者和对照组（有或无Li）的节律幅度和周期。BD病例的基线期长于对照组。1 mM的Li使对照组的振幅增加了36%，但在BD病例中未能做到这一点。在BD病例和对照组中，Li 10 mM均延长了时间。时钟基因变异分析显示，PER3和RORA基因型预测Li的周期延长，而GSK 3 β基因型预测Li的节律效应，特别是在BD病例中。通过临床病史对BD病例的分析显示，来自过去自杀未遂者的细胞更可能在Li 1 mM时显示周期延长。最后，Li增强了阻尼节律的恢复，表明Li可以治疗BD的机制。我们的工作表明，生物钟对Li的反应可能与BD的分子病理学有关。
Bipolar disorder (BD) is associated with abnormal circadian rhythms. In treatment responsive BD patients, lithium (Li) stabilizes mood and reduces suicide risk. Li also affects circadian rhythms and expression of ‘clock genes' that control them. However, the extent to which BD, Li and the circadian clock share common biological mechanisms is unknown, and there have been few direct measurements of clock gene function in samples from BD patients. Hence, the role of clock genes in BD and Li treatment remains unclear. Skin fibroblasts from BD patients (N=19) or healthy controls (N=19) were transduced with Per2::luc, a rhythmically expressed, bioluminescent circadian clock reporter gene, and rhythms were measured for 5 consecutive days. Rhythm amplitude and period were compared between BD cases and controls with and without Li. Baseline period was longer in BD cases than in controls. Li 1 mM increased amplitude in controls by 36%, but failed to do so in BD cases. Li 10 mM lengthened period in both BD cases and controls. Analysis of clock gene variants revealed that PER3 and RORA genotype predicted period lengthening by Li, whereas GSK3β genotype predicted rhythm effects of Li, specifically among BD cases. Analysis of BD cases by clinical history revealed that cells from past suicide attempters were more likely to show period lengthening with Li 1 mM. Finally, Li enhanced the resynchronization of damped rhythms, suggesting a mechanism by which Li could act therapeutically in BD. Our work suggests that the circadian clock's response to Li may be relevant to molecular pathology of BD.
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影响因子：
11
作者：
Logue, M. W.;Baldwin, C.;Guffanti, G.;Melista, E.;Wolf, E. J.;Reardon, A. F.;Uddin, M.;Wildman, D.;Galea, S.;Koenen, K. C.;Miller, M. W.
通讯作者：
Miller, M. W.
DOI：
10.1073/pnas.0811410106
发表时间：
2008-12-30
影响因子：
11.1
作者：
Hirota, Tsuyoshi;Lewis, Warren G.;Kay, Steve A.
通讯作者：
Kay, Steve A.
影响因子：
2.8
作者：
Kovanen, Leena;Saarikoski, Sirkku T.;Partonen, Timo
通讯作者：
Partonen, Timo
DOI：
10.1002/ajmg.b.30498
发表时间：
2007-04-05
影响因子：
2.8
作者：
Lachman, Herbert M.;Pedrosa, Erika;Stopkova, Pavla
通讯作者：
Stopkova, Pavla
影响因子：
3.5
作者：
Johansson, Anne-Sofie;Brask, Johan;Lundkvist, Gabriella B. S.
通讯作者：
Lundkvist, Gabriella B. S.