Pre-silencing of genes involved in the electron transport chain (ETC) pathway is associated with responsiveness to abatacept in rheumatoid arthritis

Autor: Céline Derambure, Olivier Vittecoq, Nicolas Vergne, Maria Antonietta D'Agostino, G. Dzangue-Tchoupou, Philippe Musette, Thierry Lequerré, Caroline Bérard, Martine Hiron
Přispěvatelé: Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU), Laboratoire de Mathématiques Raphaël Salem (LMRS), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Service de Rhumatologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Service de rhumatologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Adult
Male
0301 basic medicine
Settore MED/16 - REUMATOLOGIA
lcsh:Diseases of the musculoskeletal system
Microarray
Drug Resistance
Oxydative stress
Context (language use)
Bioinformatics
Arthritis
Rheumatoid
Abatacept
03 medical and health sciences
NDUFA4
0302 clinical medicine
Abatacept response
Rheumatoid
medicine
Humans
Gene silencing
Rheumatoid arthritis
Gene
Aged
030203 arthritis & rheumatology
[STAT.AP]Statistics [stat]/Applications [stat.AP]
business.industry
Arthritis
Gene Expression Profiling
Middle Aged
medicine.disease
[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Mitochondria
3. Good health
Methotrexate
030104 developmental biology
Electron Transport Chain Complex Proteins
Antirheumatic Agents
Female
lcsh:RC925-935
DNA microarray
Transcriptome
business
[STAT.ME]Statistics [stat]/Methodology [stat.ME]
Biomarkers
Research Article
medicine.drug
Zdroj: Arthritis Research and Therapy
Arthritis Research and Therapy, BioMed Central, 2017, 19 (1), ⟨10.1186/s13075-017-1319-8⟩
Arthritis Research & Therapy, Vol 19, Iss 1, Pp 1-13 (2017)
Arthritis Research & Therapy
ISSN: 1478-6354
DOI: 10.1186/s13075-017-1319-8⟩
Popis: Background In the current context of personalized medicine, one of the major challenges in the management of rheumatoid arthritis (RA) is to identify biomarkers that predict drug responsiveness. From the European APPRAISE trial, our main objective was to identify a gene expression profile associated with responsiveness to abatacept (ABA) + methotrexate (MTX) and to understand the involvement of this signature in the pathophysiology of RA. Methods Whole human genome microarrays (4 × 44 K) were performed from a first subset of 36 patients with RA. Data validation by quantitative reverse-transcription (qRT)-PCR was performed from a second independent subset of 32 patients with RA. Gene Ontology and WikiPathways database allowed us to highlight the specific biological mechanisms involved in predicting response to ABA/MTX. Results From the first subset of 36 patients with RA, a combination including 87 transcripts allowed almost perfect separation between responders and non-responders to ABA/MTX. Next, the second subset of patients 32 with RA allowed validation by qRT-PCR of a minimal signature with only four genes. This latter signature categorized 81% of patients with RA with 75% sensitivity, 85% specificity and 85% negative predictive value. This combination showed a significant enrichment of genes involved in electron transport chain (ETC) pathways. Seven transcripts from ETC pathways (NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1) were significantly downregulated in responders versus non-responders to ABA/MTX. Moreover, dysregulation of these genes was independent of inflammation and was specific to ABA response. Conclusion Pre-silencing of ETC genes is associated with future response to ABA/MTX and might be a crucial key to susceptibility to ABA response. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1319-8) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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