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Background <p>Plasma is the most used clinical specimen, yet diurnal variation in plasma proteins remains largely unexplored. We aimed to identify diurnally-regulated proteins in healthy individuals and assess their potential diagnostic implications, and highlight how diurnal awareness can advance future biomarker research.</p> Methods <p>Twenty-four healthy young individuals were studied under highly controlled conditions. Venous blood was drawn every three hours over a 24-h period, yielding 216 samples, of which 208 high-quality plasma samples were analyzed via high-throughput mass spectrometry. The missing data were filtered and imputed, and rhythmicity was assessed using Cosinor-based modeling with Benjamini–Hochberg correction. Tissue and pathway enrichment analyses were performed using the DAVID functional annotation tool.</p> Findings <p>Of 523 proteins that passed quality thresholds, 138 (~ 26%) exhibited significant diurnal oscillations. Tissue enrichment analysis revealed that most rhythmic proteins originated from the liver and platelets, with additional enrichment in a variety of tissue types. Pathway enrichment showed diurnal regulation of hemostasis, immune signaling, integrin-mediated processes, glucose metabolism, and protein synthesis. Notably, 36 clinically utilized biomarkers, including albumin, amylase, and cystatin C exhibited diurnal variation, suggesting that failing to account for temporal fluctuations may reduce diagnostic precision.</p> Interpretation <p>These findings demonstrate that over one-quarter of the human plasma proteome is under diurnal control. Such oscillations might have direct clinical implications, as the time-of-day may alter biomarker accuracy. Incorporating diurnal timing into diagnostic and research protocols, through standardized sampling or time-sensitive reference intervals, could improve patient care and inform future biomarker discoveries. Further research in larger, more diverse populations is needed to generalize these results and streamline practices in a way that takes diurnal variation into account.</p>

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Diurnal rhythm of the human plasma proteome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月22日

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  • Elvar M. S. Jóhönnuson,
  • Henriette P. Sennels,
  • Henrik L. Jørgensen,
  • Jens Hannibal,
  • Ching-Yan Chloé Yeung,
  • Christine Rasmussen,
  • Gabriela Zofia Prus,
  • Nicolai J. Wewer Albrechtsen,
  • Annelaura Bach Nielsen

摘要

Background

Plasma is the most used clinical specimen, yet diurnal variation in plasma proteins remains largely unexplored. We aimed to identify diurnally-regulated proteins in healthy individuals and assess their potential diagnostic implications, and highlight how diurnal awareness can advance future biomarker research.

Methods

Twenty-four healthy young individuals were studied under highly controlled conditions. Venous blood was drawn every three hours over a 24-h period, yielding 216 samples, of which 208 high-quality plasma samples were analyzed via high-throughput mass spectrometry. The missing data were filtered and imputed, and rhythmicity was assessed using Cosinor-based modeling with Benjamini–Hochberg correction. Tissue and pathway enrichment analyses were performed using the DAVID functional annotation tool.

Findings

Of 523 proteins that passed quality thresholds, 138 (~ 26%) exhibited significant diurnal oscillations. Tissue enrichment analysis revealed that most rhythmic proteins originated from the liver and platelets, with additional enrichment in a variety of tissue types. Pathway enrichment showed diurnal regulation of hemostasis, immune signaling, integrin-mediated processes, glucose metabolism, and protein synthesis. Notably, 36 clinically utilized biomarkers, including albumin, amylase, and cystatin C exhibited diurnal variation, suggesting that failing to account for temporal fluctuations may reduce diagnostic precision.

Interpretation

These findings demonstrate that over one-quarter of the human plasma proteome is under diurnal control. Such oscillations might have direct clinical implications, as the time-of-day may alter biomarker accuracy. Incorporating diurnal timing into diagnostic and research protocols, through standardized sampling or time-sensitive reference intervals, could improve patient care and inform future biomarker discoveries. Further research in larger, more diverse populations is needed to generalize these results and streamline practices in a way that takes diurnal variation into account.