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

Carini, C. , Hunter, E., Ramadass, A. S., Green, J., Akoulitchev, A., McInnes, I. B. and 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), 18. (doi:10.1186/s12967-018-1387-9) (PMID:29378619) (PMCID:PMC5789697)

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Abstract

Background: There is a pressing need in rheumatoid arthritis (RA) to identify patients who will not respond to first-line disease-modifying anti-rheumatic drugs (DMARD). We explored whether differences 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 specific 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 refined 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-specific eQTL. Results: We identified 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-specific 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 stratification of response to MTX is possible, offering a mechanism to provide alternative treatments for non-responders to MTX earlier in the course of the disease.

Item Type:Articles
Keywords:Chromatin conformation signatures (CCS), DMARDs (synthetic), early rheumatoid arthritis, expression quantitative trait loci (eQTL), methotrexate, methotrexate (MTX), precision medicine drug response biomarkers, rheumatoid arthritis.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Goodyear, Professor Carl
Authors: Carini, C., Hunter, E., Ramadass, A. S., Green, J., Akoulitchev, A., McInnes, I. B., and Goodyear, C. S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Translational Medicine
Publisher:BioMed Central
ISSN:1479-5876
ISSN (Online):1479-5876
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Journal of Translational Medicine 16(1):18
Publisher Policy:Reproduced under a Creative Commons License

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