Circadian protein expression patterns in healthy young adults.

Objectives: To explore how the blood plasma proteome fluctuates across the 24-hour day and identify a subset of proteins that show endogenous circadian rhythmicity.
Methods: Plasma samples from 17 healthy adults were collected hourly under controlled conditions designed to unmask endogenous circadian rhythmicity; in a subset of 8 participants, we also collected samples across a day on a typical sleep-wake schedule. A total of 6916 proteins were analyzed from each sample using the SomaScan aptamer-based multiplexed platform. We used differential rhythmicity analysis based on a cosinor model with mixed effects to identify a subset of proteins that showed circadian rhythmicity in their abundance.
Results: One thousand and sixty-three (15%) proteins exhibited significant daily rhythmicity. Of those, 431 (6.2%) proteins displayed consistent endogenous circadian rhythms on both a sleep-wake schedule and under controlled conditions: it included both known and novel proteins. When models were fitted with two harmonics, an additional 259 (3.7%) proteins exhibited significant endogenous circadian rhythmicity, indicating that some rhythmic proteins cannot be solely captured by a simple sinusoidal model. Overall, we found that the largest number of proteins had their peak levels in the late afternoon/evening, with another smaller group peaking in the early morning.
Conclusions: This study reveals that hundreds of plasma proteins exhibit endogenous circadian rhythmicity in humans. Future analyses will likely reveal novel physiological pathways regulated by circadian clocks and pave the way for improved diagnosis and treatment for patients with circadian disorders and other pathologies. It will also advance efforts to include knowledge about time-of-day, thereby incorporating circadian medicine into personalized medicine.
Competing Interests: Declaration of conflicts of interest Mr. Specht and Mr. Kolosov, and Drs. Arrona-Palacios, Bueno, Cederberg, Duffy, Pardilla-Delgado, Ruiz-Herrera, Zeitzer, and Zitting, declare no conflict of interest. Dr. Pardilla-Delgado is currently employed by Vanda Pharmaceuticals, but this work is unrelated to his position there. Dr. Kramer’s institution has issued patents (PCT/EP2018/066771) related to biomarkers for detecting the clock. This intellectual property has been licensed by BodyClock Technologies GmbH, in which Dr. Kramer is a shareholder. Dr. Mignot occasionally consults and has received contracts from Jazz Pharmaceuticals, Orexia/Centessa, Takeda and ActiGraph; has received grant/clinical trial funding from Harmony, Takeda, Apple, Huami, Sunovion, Idorsia, Eisai; is and has been a Principal Investigator on clinical trials using oxybate salts, orexin agonists and Solriamfetol, Pharmaceutical products, for the treatment of Type 1 narcolepsy; all outside the scope of this work. Dr. Czeisler serves as the incumbent of an endowed professorship provided to Harvard Medical School by Cephalon, Inc., and reports institutional support for a Quality Improvement Initiative from Delta Airlines and Puget Sound Pilots; education support to Harvard Medical School Division of Sleep Medicine and support to Brigham and Women’s Hospital from: Jazz Pharmaceuticals PLC, Inc, Philips Respironics, Inc., Optum, and ResMed, Inc.; research support to Brigham and Women’s Hospital from Axome Therapeutics, Inc., Dayzz Ltd., Peter Brown and Margaret Hamburg, Regeneron Pharmaceuticals, Sanofi SA, Casey Feldman Foundation, Summus, Inc., Takeda Pharmaceutical Co., LTD, Abbaszadeh Foundation, CDC Foundation; educational funding to the Sleep and Health Education Program of the Harvard Medical School Division of Sleep Medicine from ResMed, Inc., Teva Pharmaceuticals Industries, Ltd., and Vanda Pharmaceuticals; personal royalty payments on sales of the Actiwatch-2 and Actiwatch-Spectrum devices from Philips Respironics, Inc; personal consulting fees from Axsome, Inc., Bryte Foundation, With Deep, Inc., and Vanda Pharmaceuticals, the Institute of Digital Media and Child Development, the Klarman Family Foundation, and the UK Biotechnology and Biological Sciences Research Council; honoraria from the Associated Professional Sleep Societies, the Massachusetts Medical Society, the National Council for Mental Wellbeing, and the National Sleep Foundation; lecture fees from Teva Pharma Australia PTY Ltd. and Emory University. Dr. Czeisler has received personal fees for serving as an expert witness on a number of civil matters, criminal matters, and arbitration cases, including those involving the following commercial and government entities: Amtrak; Bombardier, Inc.; C&J Energy Services; Dallas Police Association; Delta Airlines/Comair; Enterprise Rent-A-Car; FedEx; Greyhound Lines, Inc./Motor Coach Industries/FirstGroup America; PAR Electrical Contractors, Inc.; Puget Sound Pilots; and the San Francisco Sheriff’s Department; Schlumberger Technology Corp.; Union Pacific Railroad; United Parcel Service; Vanda Pharmaceuticals. Dr. Czeisler has received travel support from the Stanley Ho Medical Development Foundation, Merck Sharpe and Dohme; equity interest in Vanda Pharmaceuticals, With Deep, Inc, and Signos, Inc.; and institutional educational gifts to Brigham and Women’s Hospital from Johnson & Johnson, Mary Ann and Stanley Snider via Combined Jewish Philanthropies, Alexandra Drane, DR Capital, Harmony Biosciences, LLC, San Francisco Bar Pilots, Whoop, Inc., Harmony Biosciences LLC, Eisai Co., LTD, Idorsia Pharmaceuticals LTD, Sleep Number Corp., Apnimed, Inc., Avadel Pharmaceuticals, Bryte Foundation, f.lux Software, LLC, and the Stuart F. and Diana L. Quan Charitable Fund. Dr Czeisler's interests, which are all outside the scope of this work, were reviewed and are managed by the Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict-of interest policies.
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