Refinement of saliva microRNA biomarkers for sports-related concussion |
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| Institution: | 1. Department of Pediatrics, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA;2. Department of Orthopaedics and Rehabilitation, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA;3. Department of Family Medicine, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA;4. Department of Emergency Medicine, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA;5. Department of Research and Development, Quadrant Biosciences Inc., Syracuse, NY 13210, USA;6. Department of Biology, Marist College, Poughkeepsie, NY 12601, USA;7. Sports Concussion Center, College of Medicine, Vanderbilt University, Nashville, TN 37212, USA;8. Department of Family Medicine, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY 11568, USA;9. Department of Athletic Training, Colgate University, Hamilton, NY 13346, USA;10. Department of Rehabilitation Sciences, Old Dominion University, Norfolk, VA 23529, USA;11. Department of Physical Therapy Education, Orthopedics, and Neuroscience, College of Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, USA;12. Department of Exercise Science, Syracuse University, Syracuse, NY 13210, USA;13. Department of Medical Research—West, Walter Reed Army Institute of Research, US Army Joint Base Lewis-McChord, Hillhurst, WA 98433, USA |
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| Abstract: | BackgroundRecognizing sport-related concussion (SRC) is challenging and relies heavily on subjective symptom reports. An objective, biological marker could improve recognition and understanding of SRC. There is emerging evidence that salivary micro-ribonucleic acids (miRNAs) may serve as biomarkers of concussion; however, it remains unclear whether concussion-related miRNAs are impacted by exercise. We sought to determine whether 40 miRNAs previously implicated in concussion pathophysiology were affected by participation in a variety of contact and non-contact sports. Our goal was to refine a miRNA-based tool capable of identifying athletes with SRC without the confounding effects of exercise.MethodsThis case-control study harmonized data from concussed and non-concussed athletes recruited across 10 sites. Levels of salivary miRNAs within 455 samples from 314 individuals were measured with RNA sequencing. Within-subjects testing was used to identify and exclude miRNAs that changed with either (a) a single episode of exercise (166 samples from 83 individuals) or (b) season-long participation in contact sports (212 samples from 106 individuals). The miRNAs that were not impacted by exercise were interrogated for SRC diagnostic utility using logistic regression (172 samples from 75 concussed and 97 non-concussed individuals).ResultsTwo miRNAs (miR-532-5p and miR-182-5p) decreased (adjusted p < 0.05) after a single episode of exercise, and 1 miRNA (miR-4510) increased only after contact sports participation. Twenty-three miRNAs changed at the end of a contact sports season. Two of these miRNAs (miR-26b-3p and miR-29c-3p) were associated (R > 0.50; adjusted p < 0.05) with the number of head impacts sustained in a single football practice. Among the 15 miRNAs not confounded by exercise or season-long contact sports participation, 11 demonstrated a significant difference (adjusted p < 0.05) between concussed and non-concussed participants, and 6 displayed moderate ability (area under curve > 0.70) to identify concussion. A single ratio (miR-27a-5p/miR-30a-3p) displayed the highest accuracy (AUC = 0.810, sensitivity = 82.4%, specificity = 73.3%) for differentiating concussed and non-concussed participants. Accuracy did not differ between participants with SRC and non-SRC (z = 0.5, p = 0.60).ConclusionSalivary miRNA levels may accurately identify SRC when not confounded by exercise. Refinement of this approach in a large cohort of athletes could eventually lead to a non-invasive, sideline adjunct for SRC assessment. |
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