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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.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.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 LINC02549 rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (per-allele ORMeta=0.83, P Meta=0.000077; P Het=0.61). In addition, we found that each copy of the LRRC55 rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; P Het=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; P Het=0.45; P Interaction=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 MAFB rs6071980 and CNTN5 rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; P Het=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; P Het=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; P Het=0.12; P Interaction=0.032). Mechanistically, we found that subjects carrying the LINC02549 rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549 rs7767069T/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 LRRC55 rs717117G 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_US
dc.rightsAttribution 4.0 International*
dc.subjectTNF inhibitorsen_US
dc.subjectdrug responseen_US
dc.subjectgenetic varianten_US
dc.subjectrheumatoid arthritisen_US
dc.titleValidation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts.en_US
dc.contributor.departmentCiiM, Zentrum für individualisierte Infektionsmedizin, Feodor-Lynen-Str.7, 30625 Hannover.en_US
dc.identifier.journalFrontiers in immunologyen_US
dc.source.journaltitleFrontiers in immunology

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Attribution 4.0 International
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