Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts
Authors: Sánchez-Maldonado Jose Manuel , Cáliz Rafael , López-Nevot Miguel Ángel , Cabrera-Serrano Antonio José , Moñiz-Díez Ana , Canhão Helena , Ter Horst Rob , Quartuccio Luca , Sorensen Signe B. , Glintborg Bente , Hetland Merete L. , Filipescu Ileana , Pérez-Pampin Eva , Conesa-Zamora Pablo , Swierkot Jerzy , den Broeder Alfons A. , De Vita Salvatore , Petersen Eva Rabing Brix , Li Yang , Ferrer Miguel A. , Escudero Alejandro , Netea Mihai G. , Coenen Marieke J. H. , Andersen Vibeke , Fonseca João E. , Jurado Manuel , Bogunia-Kubik Katarzyna , Collantes Eduardo , Sainz Juan 
Published: October 2021

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 (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 theLINC02549rs7767069SNP 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 theLRRC55rs717117Gallele 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 theMAFBrs6071980andCNTN5rs1813443SNPs 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 theLINC02549rs7767069Tallele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of theLINC02549rs7767069T/Tgenotype showed significantly increased levels of soluble scavengers CD5 and CD6 in serum (P=0.00037 andP=0.00041). In addition, carriers of theLRRC55rs717117Gallele showed decreased production of IL6 after stimulation of PBMCs withB burgdorferiandE colibacteria (P=0.00046 andP=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 theLINC02549andLRRC55loci to determine the response to TNFi in RA patients and suggested a weak effect of theMAFB and CNTN5loci that need to be further investigated.