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J Transl Med. 2018 Jan 29;16(1):18. doi: 10.1186/s12967-018-1387-9.

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

Author information

1
Pfizer Inc., Cambridge, USA. claudio.carini@kcl.ac.uk.
2
Department of Asthma, Allergy & Lung Biology, GSTT Campus, King's College School of Medicine, London, UK. claudio.carini@kcl.ac.uk.
3
Oxford BioDynamics Plc, Oxford, UK.
4
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.

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.

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

PMID:
29378619
PMCID:
PMC5789697
DOI:
10.1186/s12967-018-1387-9
[Indexed for MEDLINE]
Free PMC Article

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