Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis

Claudio Carini; Ewan Hunter; Scottish Early Rheumatoid Arthritis Inception cohort Investigators; Aroul S. Ramadass; Jayne Green; Alexandre Akoulitchev; Iain B. McInnes; Carl S. Goodyear

doi:10.1186/s12967-018-1387-9

Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis

Claudio Carini, Ewan Hunter, Scottish Early Rheumatoid Arthritis Inception cohort Investigators, Aroul S. Ramadass, Jayne Green, Alexandre Akoulitchev, Iain B. McInnes, Carl S. Goodyear

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

18 Downloads (Pure)

Abstract

Background: There is a pressing need in rheumatoid arthritis (RA) to identify patients who will not respond to frstline disease-modifying anti-rheumatic drugs (DMARD). We explored whether diferences in genomic architecture represented by a chromosome conformation signature (CCS) in blood taken from early RA patients before methotrexate (MTX) treatment could assist in identifying non-response to DMARD and, whether there is an association between such a signature and RA specifc expression quantitative trait loci (eQTL).
Methods: We looked for the presence of a CCS in blood from early RA patients commencing MTX using chromosome conformation capture by EpiSwitch™. Using blood samples from MTX responders, non-responders and healthy controls, a custom designed biomarker discovery array was refned to a 5-marker CCS that could discriminate between responders and non-responders to MTX. We cross-validated the predictive power of the CCS by generating 150 randomized groups of 59 early RA patients (30 responders and 29 non-responders) before MTX treatment. The CCS was validated using a blinded, independent cohort of 19 early RA patients (9 responders and 10 non-responders). Last, the loci of the CCS markers were mapped to RA-specifc eQTL.
Results: We identifed a 5-marker CCS that could identify, at baseline, responders and non-responders to MTX. The CCS consisted of binary chromosome conformations in the genomic regions of IFNAR1, IL-21R, IL-23, CXCL13 and IL-17A. When tested on a cohort of 59 RA patients, the CCS provided a negative predictive value of 90.0% for MTX response. When tested on a blinded independent validation cohort of 19 early RA patients, the signature demonstrated a true negative response rate of 86 and a 90% sensitivity for detection of non-responders to MTX. Only conformations in responders mapped to RA-specifc eQTL.
Conclusions: Here we demonstrate that detection of a CCS in blood in early RA is able to predict inadequate response to MTX with a high degree of accuracy. Our results provide a proof of principle that a priori stratifcation of response to MTX is possible, ofering a mechanism to provide alternative treatments for non-responders to MTX earlier in the course of the disease.

Original language	English
Article number	18
Pages (from-to)	1-11
Number of pages	11
Journal	Journal of translational medicine
Volume	16
DOIs	https://doi.org/10.1186/s12967-018-1387-9
Publication status	Published - 29 Jan 2018

Bibliographical note

The authors would like to thank members of OBD Reference Facility Benjamin
Foulkes, Chloe Bird, Emily Corfeld and Matthew Salter for expedient
processing of clinical samples on the EpiSwitch™ platform and Magdalena
Jeznach and Willem Westra for help with preparation of the manuscript. The
study employed samples from the SERA Biobank used with permission and
approval of the SERA Approval Group. We gratefully acknowledge the invaluable
contribution of the clinicians and operating team in SERA. We would
also like to thank Prof. Raju Kucherlapati (Harvard Medical School), and Prof.
Jane Mellor (Oxford Univ.), Prof. John O’Shea (National Institute of Health) and
Prof. John Isaacs (New Castle Univ.) for their independent and critical review
of our study.
A list of Scottish Early Rheumatoid Arthritis (SERA) inception cohort investigators
is provided in Additional fle 1: Additional Note.

Funding
This work was funded by Oxford BioDynamics.

Keywords

Early rheumatoid arthritis
Methotrexate
Rheumatoid arthritis
DMARDs (synthetic)
Precision medicine drug response biomarkers
Methotrexate (MTX)
Chromatin conformation signatures (CCS)
Expression quantitative trait loci (eQTL)

Access to Document

10.1186/s12967-018-1387-9Licence: CC BY

Chromosome conformation signatures defne predictive markers of inadequate response to methotrexate in early rheumatoid arthritis
© The Author(s) 2018. 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.
Final published version, 1.32 MBLicence: CC BY

Cite this

Carini, C., Hunter, E., Scottish Early Rheumatoid Arthritis Inception cohort Investigators, Ramadass, A. S., Green, J., Akoulitchev, A., McInnes, I. B., & Goodyear, C. S. (2018). Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis. Journal of translational medicine, 16, 1-11. Article 18. https://doi.org/10.1186/s12967-018-1387-9

Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis. / Carini, Claudio; Hunter, Ewan; Scottish Early Rheumatoid Arthritis Inception cohort Investigators et al.
In: Journal of translational medicine, Vol. 16, 18, 29.01.2018, p. 1-11.

Research output: Contribution to journal › Article › peer-review

Carini, C, Hunter, E, Scottish Early Rheumatoid Arthritis Inception cohort Investigators, Ramadass, AS, Green, J, Akoulitchev, A, McInnes, IB & Goodyear, CS 2018, 'Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis', Journal of translational medicine, vol. 16, 18, pp. 1-11. https://doi.org/10.1186/s12967-018-1387-9

@article{5039f046fa064324a84d4435d58e1896,

title = "Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis",

abstract = "Background: There is a pressing need in rheumatoid arthritis (RA) to identify patients who will not respond to frstline disease-modifying anti-rheumatic drugs (DMARD). We explored whether diferences in genomic architecture represented by a chromosome conformation signature (CCS) in blood taken from early RA patients before methotrexate (MTX) treatment could assist in identifying non-response to DMARD and, whether there is an association between such a signature and RA specifc expression quantitative trait loci (eQTL).Methods: We looked for the presence of a CCS in blood from early RA patients commencing MTX using chromosome conformation capture by EpiSwitch{\texttrademark}. Using blood samples from MTX responders, non-responders and healthy controls, a custom designed biomarker discovery array was refned to a 5-marker CCS that could discriminate between responders and non-responders to MTX. We cross-validated the predictive power of the CCS by generating 150 randomized groups of 59 early RA patients (30 responders and 29 non-responders) before MTX treatment. The CCS was validated using a blinded, independent cohort of 19 early RA patients (9 responders and 10 non-responders). Last, the loci of the CCS markers were mapped to RA-specifc eQTL.Results: We identifed a 5-marker CCS that could identify, at baseline, responders and non-responders to MTX. The CCS consisted of binary chromosome conformations in the genomic regions of IFNAR1, IL-21R, IL-23, CXCL13 and IL-17A. When tested on a cohort of 59 RA patients, the CCS provided a negative predictive value of 90.0% for MTX response. When tested on a blinded independent validation cohort of 19 early RA patients, the signature demonstrated a true negative response rate of 86 and a 90% sensitivity for detection of non-responders to MTX. Only conformations in responders mapped to RA-specifc eQTL.Conclusions: Here we demonstrate that detection of a CCS in blood in early RA is able to predict inadequate response to MTX with a high degree of accuracy. Our results provide a proof of principle that a priori stratifcation of response to MTX is possible, ofering a mechanism to provide alternative treatments for non-responders to MTX earlier in the course of the disease.",

keywords = "Early rheumatoid arthritis, Methotrexate, Rheumatoid arthritis, DMARDs (synthetic), Precision medicine drug response biomarkers, Methotrexate (MTX), Chromatin conformation signatures (CCS), Expression quantitative trait loci (eQTL)",

author = "Claudio Carini and Ewan Hunter and {Scottish Early Rheumatoid Arthritis Inception cohort Investigators} and Ramadass, {Aroul S.} and Jayne Green and Alexandre Akoulitchev and McInnes, {Iain B.} and Goodyear, {Carl S.} and Janet Liversidge and David Reid and Neil Basu",

note = "The authors would like to thank members of OBD Reference Facility Benjamin Foulkes, Chloe Bird, Emily Corfeld and Matthew Salter for expedient processing of clinical samples on the EpiSwitch{\texttrademark} platform and Magdalena Jeznach and Willem Westra for help with preparation of the manuscript. The study employed samples from the SERA Biobank used with permission and approval of the SERA Approval Group. We gratefully acknowledge the invaluable contribution of the clinicians and operating team in SERA. We would also like to thank Prof. Raju Kucherlapati (Harvard Medical School), and Prof. Jane Mellor (Oxford Univ.), Prof. John O{\textquoteright}Shea (National Institute of Health) and Prof. John Isaacs (New Castle Univ.) for their independent and critical review of our study. A list of Scottish Early Rheumatoid Arthritis (SERA) inception cohort investigators is provided in Additional fle 1: Additional Note. Funding This work was funded by Oxford BioDynamics.",

year = "2018",

month = jan,

day = "29",

doi = "10.1186/s12967-018-1387-9",

language = "English",

volume = "16",

pages = "1--11",

journal = "Journal of translational medicine",

issn = "1479-5876",

publisher = "BioMed Central",

}

TY - JOUR

T1 - Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis

AU - Carini, Claudio

AU - Hunter, Ewan

AU - Scottish Early Rheumatoid Arthritis Inception cohort Investigators

AU - Ramadass, Aroul S.

AU - Green, Jayne

AU - Akoulitchev, Alexandre

AU - McInnes, Iain B.

AU - Goodyear, Carl S.

AU - Liversidge, Janet

AU - Reid, David

AU - Basu, Neil

N1 - The authors would like to thank members of OBD Reference Facility Benjamin Foulkes, Chloe Bird, Emily Corfeld and Matthew Salter for expedient processing of clinical samples on the EpiSwitch™ platform and Magdalena Jeznach and Willem Westra for help with preparation of the manuscript. The study employed samples from the SERA Biobank used with permission and approval of the SERA Approval Group. We gratefully acknowledge the invaluable contribution of the clinicians and operating team in SERA. We would also like to thank Prof. Raju Kucherlapati (Harvard Medical School), and Prof. Jane Mellor (Oxford Univ.), Prof. John O’Shea (National Institute of Health) and Prof. John Isaacs (New Castle Univ.) for their independent and critical review of our study. A list of Scottish Early Rheumatoid Arthritis (SERA) inception cohort investigators is provided in Additional fle 1: Additional Note. Funding This work was funded by Oxford BioDynamics.

PY - 2018/1/29

Y1 - 2018/1/29

N2 - Background: There is a pressing need in rheumatoid arthritis (RA) to identify patients who will not respond to frstline disease-modifying anti-rheumatic drugs (DMARD). We explored whether diferences in genomic architecture represented by a chromosome conformation signature (CCS) in blood taken from early RA patients before methotrexate (MTX) treatment could assist in identifying non-response to DMARD and, whether there is an association between such a signature and RA specifc expression quantitative trait loci (eQTL).Methods: We looked for the presence of a CCS in blood from early RA patients commencing MTX using chromosome conformation capture by EpiSwitch™. Using blood samples from MTX responders, non-responders and healthy controls, a custom designed biomarker discovery array was refned to a 5-marker CCS that could discriminate between responders and non-responders to MTX. We cross-validated the predictive power of the CCS by generating 150 randomized groups of 59 early RA patients (30 responders and 29 non-responders) before MTX treatment. The CCS was validated using a blinded, independent cohort of 19 early RA patients (9 responders and 10 non-responders). Last, the loci of the CCS markers were mapped to RA-specifc eQTL.Results: We identifed a 5-marker CCS that could identify, at baseline, responders and non-responders to MTX. The CCS consisted of binary chromosome conformations in the genomic regions of IFNAR1, IL-21R, IL-23, CXCL13 and IL-17A. When tested on a cohort of 59 RA patients, the CCS provided a negative predictive value of 90.0% for MTX response. When tested on a blinded independent validation cohort of 19 early RA patients, the signature demonstrated a true negative response rate of 86 and a 90% sensitivity for detection of non-responders to MTX. Only conformations in responders mapped to RA-specifc eQTL.Conclusions: Here we demonstrate that detection of a CCS in blood in early RA is able to predict inadequate response to MTX with a high degree of accuracy. Our results provide a proof of principle that a priori stratifcation of response to MTX is possible, ofering a mechanism to provide alternative treatments for non-responders to MTX earlier in the course of the disease.

AB - Background: There is a pressing need in rheumatoid arthritis (RA) to identify patients who will not respond to frstline disease-modifying anti-rheumatic drugs (DMARD). We explored whether diferences in genomic architecture represented by a chromosome conformation signature (CCS) in blood taken from early RA patients before methotrexate (MTX) treatment could assist in identifying non-response to DMARD and, whether there is an association between such a signature and RA specifc expression quantitative trait loci (eQTL).Methods: We looked for the presence of a CCS in blood from early RA patients commencing MTX using chromosome conformation capture by EpiSwitch™. Using blood samples from MTX responders, non-responders and healthy controls, a custom designed biomarker discovery array was refned to a 5-marker CCS that could discriminate between responders and non-responders to MTX. We cross-validated the predictive power of the CCS by generating 150 randomized groups of 59 early RA patients (30 responders and 29 non-responders) before MTX treatment. The CCS was validated using a blinded, independent cohort of 19 early RA patients (9 responders and 10 non-responders). Last, the loci of the CCS markers were mapped to RA-specifc eQTL.Results: We identifed a 5-marker CCS that could identify, at baseline, responders and non-responders to MTX. The CCS consisted of binary chromosome conformations in the genomic regions of IFNAR1, IL-21R, IL-23, CXCL13 and IL-17A. When tested on a cohort of 59 RA patients, the CCS provided a negative predictive value of 90.0% for MTX response. When tested on a blinded independent validation cohort of 19 early RA patients, the signature demonstrated a true negative response rate of 86 and a 90% sensitivity for detection of non-responders to MTX. Only conformations in responders mapped to RA-specifc eQTL.Conclusions: Here we demonstrate that detection of a CCS in blood in early RA is able to predict inadequate response to MTX with a high degree of accuracy. Our results provide a proof of principle that a priori stratifcation of response to MTX is possible, ofering a mechanism to provide alternative treatments for non-responders to MTX earlier in the course of the disease.

KW - Early rheumatoid arthritis

KW - Methotrexate

KW - Rheumatoid arthritis

KW - DMARDs (synthetic)

KW - Precision medicine drug response biomarkers

KW - Methotrexate (MTX)

KW - Chromatin conformation signatures (CCS)

KW - Expression quantitative trait loci (eQTL)

U2 - 10.1186/s12967-018-1387-9

DO - 10.1186/s12967-018-1387-9

M3 - Article

SN - 1479-5876

VL - 16

SP - 1

EP - 11

JO - Journal of translational medicine

JF - Journal of translational medicine

M1 - 18

ER -

Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis

Abstract

Bibliographical note

Keywords

Access to Document

Fingerprint

Cite this