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

Guan Wang, Jérôme Durussel, Jonathan Shurlock, Noriyuki Fuku, Martin Mooses, Georgie Bruinvels, Charles Pedlar, Richard Burden, Andrew Murray, Brendan Yee, Anne Keenan, John D. McClure, Pierre-Edouard Sottas, Yannis Pitsiladis

Research output: Contribution to journalArticle

Abstract

Background: Recombinant 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. Methods: Forty-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 foldchange. Adaptive model analysis was also applied to incorporate these markers for the detection of rHuEpo. Results: ALAS2, 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%). Conclusions: Current 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.
Original languageEnglish
JournalBMC Genomics
Volume18
Issue numberS8
DOIs
Publication statusPublished - 14 Nov 2017

Fingerprint

Erythropoietin
Transcriptome
Doping in Sports
Athletes
Exercise
Sensitivity and Specificity
Placebos
Gene Expression
Genes
Biomarkers

Bibliographical note

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Cite this

Wang, Guan ; Durussel, Jérôme ; Shurlock, Jonathan ; Fuku, Noriyuki ; Mooses, Martin ; Bruinvels, Georgie ; Pedlar, Charles ; Burden, Richard ; Murray, Andrew ; Yee, Brendan ; Keenan, Anne ; McClure, John D. ; Sottas, Pierre-Edouard ; Pitsiladis, Yannis. / Validation of whole-blood transcriptome signature during microdose recombinant human erythropoietin (rHuEpo) administration. In: BMC Genomics. 2017 ; Vol. 18, No. S8.
@article{d955ee7e62bf499ea42ed9e32d933260,
title = "Validation of whole-blood transcriptome signature during microdose recombinant human erythropoietin (rHuEpo) administration",
abstract = "Background: Recombinant 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. Methods: Forty-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 foldchange. Adaptive model analysis was also applied to incorporate these markers for the detection of rHuEpo. Results: ALAS2, 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{\%}). Conclusions: Current 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.",
author = "Guan Wang and J{\'e}r{\^o}me Durussel and Jonathan Shurlock and Noriyuki Fuku and Martin Mooses and Georgie Bruinvels and Charles Pedlar and Richard Burden and Andrew Murray and Brendan Yee and Anne Keenan and McClure, {John D.} and Pierre-Edouard Sottas and Yannis Pitsiladis",
note = "{\circledC} The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.",
year = "2017",
month = "11",
day = "14",
doi = "10.1186/s12864-017-4191-7",
language = "English",
volume = "18",
journal = "BMC Genomics",
issn = "1471-2164",
number = "S8",

}

Wang, G, Durussel, J, Shurlock, J, Fuku, N, Mooses, M, Bruinvels, G, Pedlar, C, Burden, R, Murray, A, Yee, B, Keenan, A, McClure, JD, Sottas, P-E & Pitsiladis, Y 2017, 'Validation of whole-blood transcriptome signature during microdose recombinant human erythropoietin (rHuEpo) administration', BMC Genomics, vol. 18, no. S8. https://doi.org/10.1186/s12864-017-4191-7

Validation of whole-blood transcriptome signature during microdose recombinant human erythropoietin (rHuEpo) administration. / Wang, Guan; Durussel, Jérôme; Shurlock, Jonathan; Fuku, Noriyuki; Mooses, Martin; Bruinvels, Georgie; Pedlar, Charles; Burden, Richard; Murray, Andrew; Yee, Brendan; Keenan, Anne; McClure, John D.; Sottas, Pierre-Edouard; Pitsiladis, Yannis.

In: BMC Genomics, Vol. 18, No. S8, 14.11.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Validation of whole-blood transcriptome signature during microdose recombinant human erythropoietin (rHuEpo) administration

AU - Wang, Guan

AU - Durussel, Jérôme

AU - Shurlock, Jonathan

AU - Fuku, Noriyuki

AU - Mooses, Martin

AU - Bruinvels, Georgie

AU - Pedlar, Charles

AU - Burden, Richard

AU - Murray, Andrew

AU - Yee, Brendan

AU - Keenan, Anne

AU - McClure, John D.

AU - Sottas, Pierre-Edouard

AU - Pitsiladis, Yannis

N1 - © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

PY - 2017/11/14

Y1 - 2017/11/14

N2 - Background: Recombinant 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. Methods: Forty-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 foldchange. Adaptive model analysis was also applied to incorporate these markers for the detection of rHuEpo. Results: ALAS2, 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%). Conclusions: Current 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.

AB - Background: Recombinant 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. Methods: Forty-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 foldchange. Adaptive model analysis was also applied to incorporate these markers for the detection of rHuEpo. Results: ALAS2, 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%). Conclusions: Current 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.

U2 - 10.1186/s12864-017-4191-7

DO - 10.1186/s12864-017-4191-7

M3 - Article

VL - 18

JO - BMC Genomics

JF - BMC Genomics

SN - 1471-2164

IS - S8

ER -