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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Journal of Translational Medicine 1/2018

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

Zeitschrift:
Journal of Translational Medicine > Ausgabe 1/2018
Autoren:
Claudio Carini, Ewan Hunter, Aroul S. Ramadass, Jayne Green, Alexandre Akoulitchev, Iain B. McInnes, Carl S. Goodyear, Scottish Early Rheumatoid Arthritis Inception cohort Investigators
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12967-018-1387-9) contains supplementary material, which is available to authorized users.
Iain B. McInnes and Carl S. Goodyear are senior authors

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.
Zusatzmaterial
Additional file 1: Note. Scottish Early Rheumatoid Arthritis inception cohort (SERA). Table S1. Previous studies on prediction of MTX response in RA. Table S2. Patient characteristics—discovery cohort. Table S3. Patient characteristics—test cohort. Table S4. Patient characteristics—blinded validation cohort. Additional Methods. Statistical analysis and details of assays used to generate the CCS. Table S5. Selected genes for EpiSwitch Array. Figure S1. Design for discovery and validation of epigenetic stratifying biomarker signature for SERA patients. Table S6. Stepwise marker selection. Table S7. 65 Selected genes from EpiSwitch Array analysis. Table S8. 12 Selected genes from EpiSwitch PCR. Figure S2. Graphical representation of the genomic co-ordinates of the CXCL13 CCS marker associated with non-response to MTX. Figure S3. Graphical representation of the genomic co-ordinates of the IL- 17A CCS marker associated with non-response to MTX. Figure S4. Graphical representation of the genomic co-ordinates of the IFNAR1 CCS marker associated with non-response to MTX. Figure S5. Graphical representation of the genomic co-ordinates of the IL- 21R CCS marker associated with non-response to MTX. Figure S6. Graphical representation of the genomic co-ordinates of the IL-23 CCS marker associated with non-response to MTX. Figure S7. Clinical characteristics of independent blinded validation cohort. Table S9. CCS markers associated with eQTLs.
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