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

Abstract

BackgroundThere 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).MethodsWe 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.ResultsWe 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.ConclusionsHere 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.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1387-9) contains supplementary material, which is available to authorized users.

Initial Identification of a Blood-Based Chromosome Conformation Signature for Aiding in the Diagnosis of Amyotrophic Lateral Sclerosis

“…EpiSwitch is a high throughput technology platform that pairs high resolution chromosome conformational capture results with regression analysis and machine learning to develop disease classifications [ 8 ]. Screening and selection of statistically significant differences in conditional and stable profiles of genome architecture associated with samples from patients suffering from a disease, in comparison to healthy control samples, serves as a way to select epigenetic biomarkers that can diagnose and stratify pathological conditions [ [8] , [9] , [10] , [11] , [12] , [13] ]. In this study, EpiSwitch was used on blood samples in a three-step process to identify, evaluate, and validate statistically-significant differences in chromosomal conformations between ALS patients and healthy controls ( Fig.…”

“…In light of this, the Northeast ALS Consortium (NEALS) Biofluid Repository was established to provide researches and industry partners with biologic samples collected from the patients using standard operating procedures (SOPs) and linked to clinical information for use in research studies [ 7 ]. In this pilot study, samples from the NEALS Biofluid Repository were analyzed using EpiSwitch , a high-resolution technology to identify structural-functional epigenetic changes in genomic architecture associated with pathological phenotypes developed by Oxford BioDynamics [ [8] , [9] , [10] , [11] , [12] , [13] ]. As multiple genomic regions contribute to phenotypic differences through changes in genomic architecture, this approach allows for the development of a chromosomal conformation signature (CCS) of alterations in genomic architecture between two states (disease vs. non-diseased, pre-treatment vs. post-treatment).…”

Precision medicine in psoriatic arthritis: how should we select targeted therapies?

“…Epigenetic and transcriptional approaches in blood or target tissue offer some promise, as do proteomic and metabolomic considerations. For example, the precision choice of therapies has already begun to be addressed in rheumatoid arthritis (RA) 48 . In RA, differences in genomic architecture represented by a chromosome conformation signature (CCS) in baseline blood samples have been shown to be predictive markers of methotrexate response 48 .…”

“…For example, the precision choice of therapies has already begun to be addressed in rheumatoid arthritis (RA) 48 . In RA, differences in genomic architecture represented by a chromosome conformation signature (CCS) in baseline blood samples have been shown to be predictive markers of methotrexate response 48 . When considering response to biologics, the ORBIT trial compared two biologics in RA with different modes of action 49 , confirming non-inferiority of rituximab (B-cell depleting therapy) compared to TNFi therapy.…”

Cutting Edge Bioinformatics and Biostatistics Approaches Are Bringing Precision Medicine and Nutrition to a New Era

“…Nowadays, in precision medicine, the use of various omics technologies beyond only genetic data is being increasingly recognized for driving improvements. Indeed, transcriptomics [9], epigenomics, metabolomics, metagenomics [10], or chromosome conformation signatures [11] have all played a successful role in providing new insights on how to improve the adaptation of therapies to patients. An increasing number of databases collect integrated personal omics [12, 13], and the volume of healthcare data is increasing exponentially.…”