Validation of whole-blood transcriptome signature during microdose recombinant human erythropoietin (rHuEpo) administration

BMC Genomics

Research

Brendan Yee¹  Pierre-Edouard Sottas²  Jonathan Shurlock³  Andrew Murray⁴  Yannis P. Pitsiladis⁵  Guan Wang⁵  Martin Mooses⁶  Noriyuki Fuku⁷  Anne Keenan⁸  Jérôme Durussel⁸  John D. McClure⁸  Georgie Bruinvels⁹  Charles Pedlar⁹  Richard Burden⁹ 

[1]Affymetrix, Santa Clara, CA, USA

[2]BioKaizen Lab SA, Monthey, Switzerland

[3]Brighton and Sussex Medical School, Brighton, UK

[4]Centre for Sports and Exercise, University of Edinburgh, Edinburgh, UK

[5]Centre of Sports Medicine for Anti-Doping Research, University of Brighton, Eastbourne, UK

[6]Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, Rome, Italy

[7]Faculty of Medicine, University of Tartu, Tartu, Estonia

[8]Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan

[9]Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

[10]School of Sport, Health and Applied Science, St Mary’s University, Twickenham, London, UK

关键词: Recombinant human erythropoietin;    Whole blood;    Transcriptome;    Altitude;    Exercise;    Athlete biological passport;   

DOI  :  10.1186/s12864-017-4191-7

来源: Springer

【 摘 要 】

BackgroundRecombinant human erythropoietin (rHuEpo) can improve human performance and is therefore frequently abused by athletes. As a result, the World Anti-Doping Agency (WADA) introduced the Athlete Biological Passport (ABP) as an indirect method to detect blood doping. Despite this progress, challenges remain to detect blood manipulations such as the use of microdoses of rHuEpo.MethodsForty-five whole-blood transcriptional markers of rHuEpo previously derived from a high-dose rHuEpo administration trial were used to assess whether microdoses of rHuEpo could be detected in 14 trained subjects and whether these markers may be confounded by exercise (n = 14 trained subjects) and altitude training (n = 21 elite runners and n = 4 elite rowers, respectively). Differential gene expression analysis was carried out following normalisation and significance declared following application of a 5% false discovery rate (FDR) and a 1.5 fold-change. Adaptive model analysis was also applied to incorporate these markers for the detection of rHuEpo.ResultsALAS2, BCL2L1, DCAF12, EPB42, GMPR, SELENBP1, SLC4A1, TMOD1 and TRIM58 were differentially expressed during and throughout the post phase of microdose rHuEpo administration. The CD247 and TRIM58 genes were significantly up- and down-regulated, respectively, immediately following exercise when compared with the baseline both before and after rHuEpo/placebo. No significant gene expression changes were found 30 min after exercise in either rHuEpo or placebo groups. ALAS2, BCL2L1, DCAF12, SLC4A1, TMOD1 and TRIM58 tended to be significantly expressed in the elite runners ten days after arriving at altitude and one week after returning from altitude (FDR > 0.059, fold-change varying from 1.39 to 1.63). Following application of the adaptive model, 15 genes showed a high sensitivity (≥ 93%) and specificity (≥ 71%), with BCL2L1 and CSDA having the highest sensitivity (93%) and specificity (93%).ConclusionsCurrent results provide further evidence that transcriptional biomarkers can strengthen the ABP approach by significantly prolonging the detection window and improving the sensitivity and specificity of blood doping detection. Further studies are required to confirm, and if necessary, integrate the confounding effects of altitude training on blood doping.

【 授权许可】

CC BY   
© The Author(s). 2017

【 图 表 】

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