1. Urine metabolome profiling of immune-mediated inflammatory diseases
- Author
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Paloma Vela Casasempere, Patricia E Carreira, Ricardo Blanco, Manuel Barreiro de Acosta, José Luis Andreu, Jordi Gratacos, Xavier Correig, Hèctor Corominas, Maria Vinaixa Crevillent, Antonio Julià Cano, Juan D Cañete, Raimon Sanmarti, Maria López Lasanta, Andres C Garcia-Montero, Eduardo Fonseca, Sara Marsal, MA Aguirre, David Moreno-Ramírez, Laia Codó, Miguel Ángel Rodríguez-Gómez, Rubén Queiro, José María Pego-Reigosa, MARIA ESTEVE, Antonio Fernandez-Nebro, Francisco J Blanco Garcia, Mercedes Alperi-López, Universidad de Cantabria, UAM. Departamento de Medicina, Instituto de Investigación del Hospital de La Princesa (IP), Universitat de Barcelona, IMID Consortium, [Alonso,A, Julià,A, Marsal,S] Rheumatology Research Group, Vall d’Hebron Hospital Research Institute, Barcelona, Spain. [Vinaixa,M, Rodríguez,MA, Beltran,A, Correig,X] Centre for Omic Sciences, COS-DEEEA-URV-IISPV, Reus, Spain. [Vinaixa,M, Correig,X] Metabolomics Platform, CIBERDEM, Reus, Spain. [Domènech,E, Ferrándiz,C] Hospital Universitari Germans Trias i Pujol, Badalona, Spain. [Domènech,E, Gilbert,JP, Nos,P, Gutiérrez Casbas,A] CIBERehd, Madrid, Spain. [Fernández-Nebro,A] UGC Reumatología, Instituto de Investigación Biomédica (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain. [Cañete,JD] Hospital Clínic de Barcelona and IDIBAPS, Barcelona, Spain. [Tornero,J] Hospital Universitario Guadalajara, Guadalajara, Spain. [Gilbert,JP, González-Álvaro,I] Hospital Universitario de la Princesa and IIS-IP, Madrid, Spain. [Nos,P] Hospital la Fe, Valencia, Spain. [Gutiérrez Casbas,A] Hospital General de Alicante, Alicante, Spain. [>Puig,L] Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. [Pinto-Tasende,JA] Complejo Hospitalario Juan Canalejo, INIBIC, A Coruña, Spain. [Blanco,R] Hospital Universitario Marqués de Valdecilla, Santander, Spain., and This work was supported by the Spanish Ministry of Economy and Competitiveness grants (IPT-010000-2010-36, PSE-010000-2006-6, and PI12/01362) and by the AGAUR FI grant (2013/00974)
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Phenomena and Processes::Metabolic Phenomena::Metabolism::Metabolic Networks and Pathways::Citric Acid Cycle [Medical Subject Headings] ,0301 basic medicine ,Enfermedades inflamatorias del intestino ,Magnetic Resonance Spectroscopy ,Metabolite ,Urine biomakers ,Autoimmune diseases ,Disease ,Urine ,Inflammatory diseases ,Ciclo del ácido cítrico ,Diseases::Digestive System Diseases::Gastrointestinal Diseases::Intestinal Diseases::Inflammatory Bowel Diseases [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Arthritis, Rheumatoid ,chemistry.chemical_compound ,Crohn Disease ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Amino Acids, Cyclic::Amino Acids, Aromatic::Phenylalanine [Medical Subject Headings] ,Metabolites ,Lupus Erythematosus, Systemic ,Glicina ,Modelos lineales ,Disease activity ,Serina ,Phenomena and Processes::Metabolic Phenomena::Metabolome [Medical Subject Headings] ,Medicine(all) ,Espectroscopía de resonancia magnética ,Malalties autoimmunitàries ,Diseases::Immune System Diseases::Autoimmune Diseases::Lupus Erythematosus, Systemic [Medical Subject Headings] ,Biochemical markers ,General Medicine ,Metabòlits ,Inflamació ,Ulcerative colitis ,Humanos ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Glycine [Medical Subject Headings] ,Metaboloma ,Rheumatoid arthritis ,Urine biomarkers ,Marcadors bioquímics ,Metabolome ,Enfermedad de crohn ,Research Article ,Medicina ,Chemicals and Drugs::Biological Factors::Biomarkers [Medical Subject Headings] ,Artritis reumatoide ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Chemistry Techniques, Analytical::Spectrum Analysis::Magnetic Resonance Spectroscopy [Medical Subject Headings] ,Diseases::Skin and Connective Tissue Diseases::Skin Diseases::Skin Diseases, Papulosquamous::Psoriasis [Medical Subject Headings] ,03 medical and health sciences ,Psoriatic arthritis ,Diseases::Musculoskeletal Diseases::Joint Diseases::Arthritis::Arthritis, Psoriatic [Medical Subject Headings] ,Psoriasis ,Lupus eritematoso sistémico ,medicine ,Humans ,Metabolomics ,Diseases::Digestive System Diseases::Gastrointestinal Diseases::Intestinal Diseases::Inflammatory Bowel Diseases::Crohn Disease [Medical Subject Headings] ,Inflammation ,business.industry ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Statistical::Linear Models [Medical Subject Headings] ,Fenilalanina ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Serine [Medical Subject Headings] ,Orina ,medicine.disease ,Biomarcadores ,030104 developmental biology ,chemistry ,Diseases::Immune System Diseases::Autoimmune Diseases::Arthritis, Rheumatoid [Medical Subject Headings] ,Case-Control Studies ,Artritis psoriásica ,Immunology ,Immune-mediated inflammatory diseases ,Colitis, Ulcerative ,business ,Biomarkers - Abstract
Background: Immune-mediated inflammatory diseases (IMIDs) are a group of complex and prevalent diseases where disease diagnostic and activity monitoring is highly challenging. The determination of the metabolite profiles of biological samples is becoming a powerful approach to identify new biomarkers of clinical utility. In order to identify new metabolite biomarkers of diagnosis and disease activity, we have performed the first large-scale profiling of the urine metabolome of the six most prevalent IMIDs: rheumatoid arthritis, psoriatic arthritis, psoriasis, systemic lupus erythematosus, Crohn's disease, and ulcerative colitis. Methods: Using nuclear magnetic resonance, we analyzed the urine metabolome in a discovery cohort of 1210 patients and 100 controls. Within each IMID, two patient subgroups were recruited representing extreme disease activity (very high vs. very low). Metabolite association analysis with disease diagnosis and disease activity was performed using multivariate linear regression in order to control for the effects of clinical, epidemiological, or technical variability. After multiple test correction, the most significant metabolite biomarkers were validated in an independent cohort of 1200 patients and 200 controls. Results: In the discovery cohort, we identified 28 significant associations between urine metabolite levels and disease diagnosis and three significant metabolite associations with disease activity (P-FDR < 0.05). Using the validation cohort, we validated 26 of the diagnostic associations and all three metabolite associations with disease activity (PFDR < 0.05). Combining all diagnostic biomarkers using multivariate classifiers we obtained a good disease prediction accuracy in all IMIDs and particularly high in inflammatory bowel diseases. Several of the associated metabolites were found to be commonly altered in multiple IMIDs, some of which can be considered as hub biomarkers. The analysis of the metabolic reactions connecting the IMID-associated metabolites showed an overrepresentation of citric acid cycle, phenylalanine, and glycine-serine metabolism pathways. Conclusions: This study shows that urine is a source of biomarkers of clinical utility in IMIDs. We have found that IMIDs show similar metabolic changes, particularly between clinically similar diseases and we have found, for the first time, the presence of hub metabolites. These findings represent an important step in the development of more efficient and less invasive diagnostic and disease monitoring methods in IMIDs.
- Published
- 2016