1. Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts
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Jose Manuel Sánchez-Maldonado, Rafael Cáliz, Miguel Ángel López-Nevot, Antonio José Cabrera-Serrano, Ana Moñiz-Díez, Helena Canhão, Rob Ter Horst, Luca Quartuccio, Signe B. Sorensen, Bente Glintborg, Merete L. Hetland, Ileana Filipescu, Eva Pérez-Pampin, Pablo Conesa-Zamora, Jerzy Swierkot, Alfons A. den Broeder, Salvatore De Vita, Eva Rabing Brix Petersen, Yang Li, Miguel A. Ferrer, Alejandro Escudero, Mihai G. Netea, Marieke J. H. Coenen, Vibeke Andersen, João E. Fonseca, Manuel Jurado, Katarzyna Bogunia-Kubik, Eduardo Collantes, Juan Sainz, [Sánchez-Maldonado,JM, Cáliz,R, Cabrera-Serrano,AJ, Moñiz-Díez,A, Jurado,M, Sainz,J] Genomic Oncology Area, Centre for Genomics and Oncological Research (GENYO), Parque tecnológico de la Salud (PTS) Granada, Granada, Spain. [Sánchez-Maldonado,JM, Sainz,J] Hematology Department, Virgen de las Nieves University Hospital, Granada, Spain. [Sánchez-Maldonado,JM, López-Nevot,MA, Sainz,J] Instituto de Investigación Biosanitaria (IBs) Granada, Granada, Spain. [Cáliz,R] Department of Rheumatology, Virgen de las Nieves University Hospital, Granada, Spain. [López-Nevot,MA] Immunology Department, Virgen de las Nieves University Hospital, Granada, Spain. [Canhão,H] EpiDoC Unit, CEDOC, NOVA Medical School and National School of Public Health, Universidade Nova de Lisboa, Lisbon, Portugal. [Canhão,H] Comprehensive Health Research Center (CHRC), NOVA Medical School, Lisbon, Portugal. [Ter Horst,R, Li,Y, Netea,MG] Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands. [Quartuccio,L, De Vita,S, Andersen,V] Department of Medical Area, Clinic of Rheumatology, University of Udine, Udine, Italy. [Sorensen,SB, Andersen,V] Molecular Diagnostic and Clinical Research Unit, IRS-Center Sonderjylland, University Hospital of Southern Jutland, Aabenraa, Denmark. [Sorensen,SB] Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. [Glintborg,B, Hetland,ML] The Danish Rheumatologic Biobank and Copenhagen Center for Arthritis Research (DANBIO) Registry, The Danish Rheumatologic Biobank and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Glostrup, Denmark. [Glintborg,B, Hetland,ML] Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [Filipescu,I] Rheumatology Department, University of Medicine and Pharmacy 'Iuliu Hatieganu', Cluj-Napoca, Romania. [Pérez-Pampin,E] Rheumatology Unit, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain. [Conesa-Zamora,P] Clinical Analysis Department, Santa Lucía University Hospital, Cartagena, Spain. [Swierkot,J] Department of Rheumatology and Internal Medicine, Wroclaw Medical University, Wroclaw, Poland. [den Broeder,AA] Radboud Institute for Health Sciences, Department of Rheumatology, Radboud University Medical Center, Nijmegen, Netherlands. [Petersen,ERB] Department of Biochemistry and Immunology, University Hospital of Southern Jutland, Aabenraa, Denmark. [Li,Y] Centre for Individualised Infection Medicine (CiiM) & Centre for Experimental and Clinical Infection Research (TWINCORE), Helmholtz-Centre for Infection Research (HZI) and The Hannover Medical School (MHH), Hannover, Germany. [Escudero,A, Collantes,E] Rheumatology Department, Reina Sofía Hospital/Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba, Córdoba, Spain. [Netea,MG] Department for Immunology & Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. [Coenen,MJH] Radboud Institute for Health Sciences, Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands. [Andersen,V] Institute of Regional Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. [Fonseca,JE] Rheumatology and Metabolic Bone Diseases Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte (CHLN), Lisbon, Portugal. [Fonseca,JE] Rheumatology Research Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon Academic Medical Center, Lisbon, Portugal. [Bogunia-Kubik,K] Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland, [Sainz,J] Department of Biochemistry and Molecular Biology I, University of Granada, Granada, Spain., This study was supported by grants PI17/02276 and PI20/01845 from Fondo de Investigaciones Sanitarias (Madrid, Spain) and by intramural funds of GENYO and FIBAO foundation (Granada, Spain). This study was also supported by the Novo Nordisk Fonden (NNF15OC0016932, VA) and Knud og Edith Eriksens Mindefond (VA) and Gigtforeningen (A2037, A3570, VA). JS and KB-K were supported by the grant No. 2016/21/B/NZ5/01901 from the National Science Centre (Poland). MGN was supported by a Spinoza grant from the Netherlands Organization for Scientific Research. YL was supported by an ERC Starting Grant (948207) and the Radboud University Medical Centre Hypatia Grant (2018) for Scientific Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., and CiiM, Zentrum für individualisierte Infektionsmedizin, Feodor-Lynen-Str.7, 30625 Hannover.
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Oncology ,Male ,rheumatoid arthritis ,Pharmacogenomic Variants ,Polimorfismo de nucleótido simple ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Interleukins::Interleukin-6 [Medical Subject Headings] ,Factor reumatoide ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Autoantibodies::Rheumatoid Factor [Medical Subject Headings] ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,drug response ,Genome-wide association study ,Linkage Disequilibrium ,Arthritis, Rheumatoid ,Cohort Studies ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,TNF inhibitors ,0302 clinical medicine ,Genotype ,Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility [Medical Subject Headings] ,Variantes farmacogenómicas ,Immunology and Allergy ,GWAS ,Registries ,Genetic variant ,Original Research ,Persons::Persons::Age Groups::Adult::Aged [Medical Subject Headings] ,0303 health sciences ,Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes [Medical Subject Headings] ,Middle Aged ,Rheumatoid factor ,Phenomena and Processes::Genetic Phenomena::Genetic Linkage::Linkage Disequilibrium [Medical Subject Headings] ,3. Good health ,Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Facultatively Anaerobic Rods::Enterobacteriaceae::Escherichia::Escherichia coli [Medical Subject Headings] ,Diseases::Musculoskeletal Diseases::Rheumatic Diseases::Arthritis, Rheumatoid [Medical Subject Headings] ,Treatment Outcome ,genetic variant ,Rheumatoid arthritis ,Cohort ,Female ,Disease Susceptibility ,Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings] ,Biomarcadores farmacológicos ,Alelos ,Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings] ,Chemicals and Drugs::Biological Factors::Biological Markers::Biomarkers, Pharmacological [Medical Subject Headings] ,Adult ,medicine.medical_specialty ,Immunology ,Drug response ,Check Tags::Male [Medical Subject Headings] ,Single-nucleotide polymorphism ,Artritis reumatoide ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Internal medicine ,medicine ,Escherichia coli ,SNP ,Humans ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Tumor Necrosis Factors [Medical Subject Headings] ,Allele ,Persons::Persons::Age Groups::Adult [Medical Subject Headings] ,Alleles ,Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Alleles [Medical Subject Headings] ,030304 developmental biology ,Aged ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment Outcome [Medical Subject Headings] ,030203 arthritis & rheumatology ,Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings] ,business.industry ,Inhibidores del factor de necrosis tumoral ,Genetic Variation ,Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings] ,RC581-607 ,medicine.disease ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Molecular Epidemiology::Genome-Wide Association Study [Medical Subject Headings] ,Check Tags::Female [Medical Subject Headings] ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings] ,Polymorphism, single nucleotide ,Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5] ,Tumor Necrosis Factor Inhibitors ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Registries [Medical Subject Headings] ,Immunologic diseases. Allergy ,business ,Biomarkers ,Genome-Wide Association Study - Abstract
This study was supported by grants PI17/02276 and PI20/01845 from Fondo de Investigaciones Sanitarias (Madrid, Spain) and by intramural funds of GENYO and FIBAO foundation (Granada, Spain). This study was also supported by the Novo Nordisk Fonden (NNF15OC0016932, VA) and Knud og Edith Eriksens Mindefond (VA) and Gigtforeningen (A2037, A3570, VA). JS and KB-K were supported by the grant No. 2016/21/B/NZ5/01901 from the National Science Centre (Poland). MGN was supported by a Spinoza grant from the Netherlands Organization for Scientific Research. YL was supported by an ERC Starting Grant (948207) and the Radboud University Medical Centre Hypatia Grant (2018) for Scientific Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., We aimed to validate the association of 28 GWAS-identified genetic variants for response to TNF inhibitors (TNFi) in a discovery cohort of 1361 rheumatoid arthritis (RA) patients monitored in routine care and ascertained through the REPAIR consortium and DANBIO registry. We genotyped selected markers and evaluated their association with response to TNFi after 6 months of treatment according to the change in disease activity score 28 (DDAS28). Next, we confirmed the most interesting results through meta-analysis of our data with those from the DREAM cohort that included 706 RA patients treated with TNFi. The meta-analysis of the discovery cohort and DREAM registry including 2067 RA patients revealed an overall association of the LINC02549rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (perallele ORMeta=0.83, PMeta=0.000077; PHet=0.61). In addition, we found that each copy of the LRRC55rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; PHet=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; PHet=0.45; PInteraction=0.00028). Interestingly, although the identified associations did not survive multiple testing correction, the metaanalysis also showed overall and RF-specific associations for the MAFBrs6071980 and CNTN5rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; PHet=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; PHet=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; PHet=0.12; PInteraction=0.032). Mechanistically, we found that subjects carrying the LINC02549rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549rs7767069T/T genotype showed significantly increased levels of soluble scavengers CD5 and CD6 in serum (P=0.00037 and P=0.00041). In addition, carriers of the LRRC55rs717117G allele showed decreased production of IL6 after stimulation of PBMCs with B burgdorferi and E coli bacteria (P=0.00046 and P=0.00044), which suggested a reduced IL6-mediated anti-inflammatory effect of this marker to worsen the response to TNFi. In conclusion, this study confirmed the influence of the LINC02549 and LRRC55 loci to determine the response to TNFi in RA patients and suggested a weak effect of the MAFB and CNTN5 loci that need to be further investigated., Instituto de Salud Carlos III PI17/02276 PI20/01845, GENYO foundation (Granada, Spain), FIBAO foundation (Granada, Spain), Novo Nordisk Foundation NNF15OC0016932, Knud og Edith Eriksens Mindefond, Gigtforeningen A2037 A3570, National Science Centre, Poland 2016/21/B/NZ5/01901, Spinoza grant from the Netherlands Organization for Scientific Research, European Research Council (ERC) European Commission 948207, Radboud University Medical Centre Hypatia Grant (2018)
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- 2021
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