AUTHOR=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 

TITLE=Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.672255

DOI=10.3389/fimmu.2021.672255

ISSN=1664-3224

ABSTRACT=<p>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 the <italic>LINC02549</italic><sub>rs7767069</sub> SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (per-allele OR<sub>Meta</sub>=0.83, <italic>P</italic><sub>Meta</sub>=0.000077; <italic>P</italic><sub>Het</sub>=0.61). In addition, we found that each copy of the <italic>LRRC55</italic><sub>rs717117G</sub> allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele OR<sub>Meta</sub>=0.67, <italic>P</italic>=0.00058; <italic>P</italic><sub>Het</sub>=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele OR<sub>Meta</sub>=1.38, <italic>P</italic>=0.10; <italic>P</italic><sub>Het</sub>=0.45; <italic>P</italic><sub>Interaction</sub>=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 <italic>MAFB</italic><sub>rs6071980</sub> and <italic>CNTN5</italic><sub>rs1813443</sub> SNPs with decreased changes in DAS28 (per-allele OR<sub>Meta_rs6071980</sub> = 0.85, <italic>P</italic>=0.0059; <italic>P</italic><sub>Het</sub>=0.63 and OR<sub>Meta_rs1813443_RF+</sub>=0.81, <italic>P</italic>=0.0059; <italic>P</italic><sub>Het</sub>=0.69 and OR<sub>Meta_rs1813443_RF-</sub>=1.00, <italic>P</italic>=0.99; <italic>P</italic><sub>Het</sub>=0.12; <italic>P</italic><sub>Interaction</sub>=0.032). Mechanistically, we found that subjects carrying the <italic>LINC02549</italic><sub>rs7767069T</sub> allele had significantly increased numbers of CD45RO+CD45RA+ T cells (<italic>P</italic>=0.000025) whereas carriers of the <italic>LINC02549</italic><sub>rs7767069T/T</sub> genotype showed significantly increased levels of soluble scavengers CD5 and CD6 in serum (<italic>P</italic>=0.00037 and <italic>P</italic>=0.00041). In addition, carriers of the <italic>LRRC55</italic><sub>rs717117G</sub> allele showed decreased production of IL6 after stimulation of PBMCs with <italic>B burgdorferi</italic> and <italic>E coli</italic> bacteria (<italic>P</italic>=0.00046 and <italic>P</italic>=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 <italic>LINC02549</italic> and <italic>LRRC55</italic> loci to determine the response to TNFi in RA patients and suggested a weak effect of the <italic>MAFB and CNTN5</italic> loci that need to be further investigated.</p>