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dc.contributor.authorSánchez Maldonado, José
dc.contributor.authorMartínez Bueno, Manuel 
dc.contributor.authorJurado Chacón, Manuel 
dc.contributor.authorLópez Nevot, Miguel Ángel 
dc.contributor.authorCáliz Cáliz, Antonio Rafael 
dc.contributor.authorSáinz Pérez, Juan 
dc.date.accessioned2020-11-17T13:37:25Z
dc.date.available2020-11-17T13:37:25Z
dc.date.issued2020-03-09
dc.identifier.citationManuel Sánchez-Maldonado, J., Martínez-Bueno, M., Canhão, H. et al. NFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors: Results from the REPAIR consortium. Sci Rep 10, 4316 (2020). [https://doi.org/10.1038/s41598-020-61331-5]es_ES
dc.identifier.urihttp://hdl.handle.net/10481/64327
dc.descriptionWe thank all participants who have agreed to participate in this study. Authors also thank Maria Dolores Casares, Angeles Molina, Carmen Oloriz for the collection of Spanish samples and Hans Jurgen Hoffmann, Marianne Thomsen, Vibeke Ostergaard Thomsen, Malene Rohr Andersen, Lise Lotte B. Laursen, Helle Jorgensen, Ram Benny Christian Dessau, Niels Steen Krogh, Ulla Vogel, Paal Skytt Andersen, Ivan Brandslund, Steffen Bank, Frederik Trier Moller, Nikolai Toft and Niels Moller Andersen for the participation in collection and purification of Danish samples. We also thank the Danish Departments of Rheumatology for their implication in the collection of clinical data from RA patients included in the DANBIO cohort and the Danish Rheumatologic Biobank. Likewise, we would like to thank Teun van Herwaarden for steroid hormone measurements in serum samples from subjects ascertained through the HFGP initiative. This work was partially supported by intramural funds of GENYO and FIBAO foundation (Granada, Spain); Novo Nordisk Fonden (NNF15OC0016932, VA); and Knud og Edith Eriksens Mindefond (VA) and Gigtforeningen (A2037, A3570, VA). MGN was supported by a Spinoza grant from the Netherlands Organization for Scientific Research.es_ES
dc.descriptionAll data used in this project have been meticulously cataloged and archived in the BBMRI-NL data infrastructure (https://hfgp.bbmri.nl/) using the MOLGENIS open source platform for scientific data45. This allows flexible data querying and download, including sufficiently rich metadata and interfaces for machine processing (R statistics, REST API) and using FAIR principles to optimize Findability, Accessibility, Interoperability and Reusability46. Genetic data from the discovery and DANBIO populations can be accessed at ftp.genyo.es and data from the DREAM registry are available at https://www.synapse.org/#!Synapse:syn3280809/wiki/194735 and https://www. synapse.org/#!Synapse:syn3280809/wiki/194736.es_ES
dc.descriptionSupplementary information is available for this paper at https://doi.org/10.1038/s41598-020-61331-5.es_ES
dc.description.abstractThis study sought to evaluate the association of 28 single nucleotide polymorphisms (SNPs) within NFKB and inflammasome pathway genes with the risk of rheumatoid arthritis (RA) and response to TNF inhibitors (TNFi). We conducted a case-control study in a European population of 1194 RA patients and 1328 healthy controls. The association of potentially interesting markers was validated with data from the DANBIO (695 RA patients and 978 healthy controls) and DREAM (882 RA patients) registries. The meta-analysis of our data with those from the DANBIO registry confirmed that anti-citrullinated protein antibodies (ACPA)-positive subjects carrying the NFKB2rs11574851T allele had a significantly increased risk of developing RA (PMeta_ACPA + = 0.0006) whereas no significant effect was found in ACPA-negative individuals (PMeta_ACPA− = 0.35). An ACPA-stratified haplotype analysis including both cohorts (n = 4210) confirmed that ACPA-positive subjects carrying the NFKB2TT haplotype had an increased risk of RA (OR = 1.39, P = 0.0042) whereas no effect was found in ACPA-negative subjects (OR = 1.04, P = 0.82). The meta-analysis of our data with those from the DANBIO and DREAM registries also revealed a suggestive association of the NFKB2rs1056890 SNP with larger changes in DAS28 (OR = 1.18, P = 0.007). Functional experiments showed that peripheral blood mononuclear cells from carriers of the NFKB2rs1005044C allele (in LD with the rs1056890, r2 = 1.00) showed increased production of IL10 after stimulation with LPS (P = 0.0026). These results provide first evidence of a role of the NFKB2 locus in modulating the risk of RA in an ACPA-dependent manner and suggest its implication in determining the response to TNFi. Additional studies are now warranted to further validate these findings.es_ES
dc.description.sponsorshipGENYOes_ES
dc.description.sponsorshipFIBAO foundation (Granada, Spain)es_ES
dc.description.sponsorshipNovo Nordisk Foundation NNF15OC0016932es_ES
dc.description.sponsorshipKnud og Edith Eriksens Mindefond A2037 A3570es_ES
dc.description.sponsorshipGigtforeningen A2037 A3570es_ES
dc.description.sponsorshipSpinoza grant from the Netherlands Organization for Scientific Researches_ES
dc.language.isoenges_ES
dc.publisherSpringer Naturees_ES
dc.rightsAtribución 3.0 España*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/*
dc.subjectDiagnostic markerses_ES
dc.subjectPrognostic markerses_ES
dc.subjectRheumatoid arthritis es_ES
dc.titleNFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors: Results from the REPAIR consortiumes_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES
dc.identifier.doi10.1038/s41598-020-61331-5
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersiones_ES


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