Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Laboratory of Chronobiology, Berlin, Germany.
Humboldt-Universität zu Berlin, Department of Biology, Systems Immunology Lab, Berlin, Germany.
J Clin Invest. 2018 Aug 31;128(9):3826-3839. doi: 10.1172/JCI120874. Epub 2018 Aug 6.
The circadian clock is a fundamental and pervasive biological program that coordinates 24-hour rhythms in physiology, metabolism, and behavior, and it is essential to health. Whereas therapy adapted to time of day is increasingly reported to be highly successful, it needs to be personalized, since internal circadian time is different for each individual. In addition, internal time is not a stable trait, but is influenced by many factors, including genetic predisposition, age, sex, environmental light levels, and season. An easy and convenient diagnostic tool is currently missing.
To establish a validated test, we followed a 3-stage biomarker development strategy: (a) using circadian transcriptomics of blood monocytes from 12 individuals in a constant routine protocol combined with machine learning approaches, we identified biomarkers for internal time; and these biomarkers (b) were migrated to a clinically relevant gene expression profiling platform (NanoString) and (c) were externally validated using an independent study with 28 early or late chronotypes.
We developed a highly accurate and simple assay (BodyTime) to estimate the internal circadian time in humans from a single blood sample. Our assay needs only a small set of blood-based transcript biomarkers and is as accurate as the current gold standard method, dim-light melatonin onset, at smaller monetary, time, and sample-number cost.
The BodyTime assay provides a new diagnostic tool for personalization of health care according to the patient's circadian clock.
This study was supported by the Bundesministerium für Bildung und Forschung, Germany (FKZ: 13N13160 and 13N13162) and Intellux GmbH, Germany.
生物钟是一种基本且普遍存在的生物程序，它协调着生理、代谢和行为的 24 小时节律，对健康至关重要。虽然适应时间的治疗方法越来越被报道是非常成功的，但它需要个性化，因为每个人的内部生物钟时间都不同。此外，内部时间不是一个稳定的特征，而是受到许多因素的影响，包括遗传倾向、年龄、性别、环境光照水平和季节。目前缺少一种简单方便的诊断工具。
为了建立一个经过验证的测试，我们遵循了一个 3 阶段的生物标志物开发策略：（a）使用 12 名个体在恒常作息方案下的血液单核细胞的生物钟转录组学，结合机器学习方法，我们确定了内部时间的生物标志物；这些生物标志物（b）迁移到一个临床相关的基因表达谱平台（NanoString），（c）并使用一个独立的研究进行外部验证，该研究涉及 28 个早或晚的生物钟类型。
我们开发了一种高度准确和简单的测定方法（BodyTime），可以从单个血液样本中估计人类的内部生物钟时间。我们的测定方法只需要一小部分基于血液的转录生物标志物，并且与当前的金标准方法——暗光褪黑素起始时间一样准确，但其在经济、时间和样本数量方面的成本要低得多。
BodyTime 测定法为根据患者的生物钟对医疗保健进行个性化提供了一种新的诊断工具。
本研究由德国联邦教育与研究部（FKZ：13N13160 和 13N13162）和德国 Intellux GmbH 资助。
