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Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis

2021-10-27Artigo científico Acesso aberto
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dc.contributor.authorSánchez-Maldonado, Jose Manuel
dc.contributor.authorCáliz, Rafael
dc.contributor.authorLópez-Nevot, Miguel Ángel
dc.contributor.authorCabrera-Serrano, Antonio José
dc.contributor.authorMoñiz-Díez, Ana
dc.contributor.authorCanhão, Helena
dc.contributor.authorCanhão, Helena
dc.contributor.authorTer Horst, Rob
dc.contributor.authorQuartuccio, Luca
dc.contributor.authorSorensen, Signe B.
dc.contributor.authorGlintborg, Bente
dc.contributor.authorHetland, Merete L
dc.contributor.authorFilipescu, Ileana
dc.contributor.authorPérez-Pampin, Eva
dc.contributor.authorConesa-Zamora, Pablo
dc.contributor.authorSwierkot, Jerzy
dc.contributor.authorden Broeder, Alfons A.
dc.contributor.authorDe Vita, Salvatore
dc.contributor.authorPetersen, Eva Rabing Brix
dc.contributor.authorLi, Yang
dc.contributor.authorFerrer, Miguel A.
dc.contributor.authorEscudero, Alejandro
dc.contributor.authorNetea, Mihai G
dc.contributor.authorCoenen, Marieke J.H.
dc.contributor.authorAndersen, Vibeke
dc.contributor.authorFonseca, João E.
dc.contributor.authorJurado, Manuel
dc.contributor.authorBogunia-Kubik, Katarzyna
dc.contributor.authorCollantes, Eduardo
dc.contributor.authorSainz, Juan
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionComprehensive Health Research Centre (CHRC) - pólo NMS
dc.contributor.institutionCentro de Estudos de Doenças Crónicas (CEDOC)
dc.contributor.pblFrontiers
dc.date.accessioned2021-12-22T23:25:40Z
dc.date.available2021-12-22T23:25:40Z
dc.date.issued2021-10-27
dc.descriptionFunding Information: We thank all participants who have agreed to participate in this study. Authors also thank Mar?a Dolores Casares, ?ngeles Molina, Carmen Oloriz for the collection of Spanish samples and Hans Jurgen Hoffmann, Marianne Thomsen, Vibeke ?stergaard Thomsen, Malene Rohr Andersen, Lise Lotte B. Laursen, Helle J?rgensen, Ram Benny Christian Dessau, Niels Steen Krogh, Ulla Vogel, Paal Skytt Andersen, Ivan Brandslund, Steffen Bank, Frederik Trier M?ller, Nikolai Toft and Niels M?ller 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. Publisher Copyright: Copyright © 2021 Sánchez-Maldonado, Cáliz, López-Nevot, Cabrera-Serrano, Moñiz-Díez, Canhão, Ter Horst, Quartuccio, Sorensen, Glintborg, Hetland, Filipescu, Pérez-Pampin, Conesa-Zamora, Swierkot, den Broeder, De Vita, Petersen, Li, Ferrer, Escudero, Netea, Coenen, Andersen, Fonseca, Jurado, Bogunia-Kubik, Collantes and Sainz.
dc.description.abstractWe 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 (ΔDAS28). 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 (per-allele 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 meta-analysis 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.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent3672133
dc.identifier.doi10.3389/fimmu.2021.672255
dc.identifier.issn1664-3224
dc.identifier.otherPURE: 34925120
dc.identifier.otherPURE UUID: d461f451-85c4-4b47-9b3f-c0069096fd2e
dc.identifier.otherScopus: 85118846234
dc.identifier.otherORCID: /0000-0003-1894-4870/work/105210318
dc.identifier.otherPubMed: 34777329
dc.identifier.otherWOS: 000719448200001
dc.identifier.urihttp://hdl.handle.net/10362/129663
dc.identifier.urlhttps://www.scopus.com/pages/publications/85118846234
dc.language.isoeng
dc.peerreviewedyes
dc.subjectdrug response
dc.subjectgenetic variant
dc.subjectGWAS
dc.subjectrheumatoid arthritis
dc.subjectTNF inhibitors
dc.subjectImmunology and Allergy
dc.subjectImmunology
dc.titleValidation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritisen
dc.title.subtitleA Meta-Analysis of Two Large Cohortsen
dc.typejournal article
degois.publication.titleFrontiers in Immunology
degois.publication.volume12
dspace.entity.typePublication
person.familyNameCanhão
person.givenNameHelena
person.identifier379800
person.identifier.ciencia-id5A17-C6D9-DBC8
person.identifier.orcid0000-0003-1894-4870
person.identifier.ridC-9611-2018
person.identifier.scopus-author-id6602393492
rcaap.rightsopenAccess
relation.isAuthorOfPublicationc87f58c0-b53d-4321-9bd7-39554e6001b5
relation.isAuthorOfPublication.latestForDiscoveryc87f58c0-b53d-4321-9bd7-39554e6001b5

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