RT Journal Article
T1 Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts
A1 Manuel Sanchez-Maldonado, Jose
A1 Caliz, Rafael
A1 Angel Lopez-Nevot, Miguel
A1 Jose Cabrera-Serrano, Antonio
A1 Moniz-Diez, Ana
A1 Canhao, Helena
A1 Ter Horst, Rob
A1 Quartuccio, Luca
A1 Sorensen, Signe B.
A1 Glintborg, Bente
A1 Hetland, Merete L.
A1 Filipescu, Ileana
A1 Perez-Pampin, Eva
A1 Conesa-Zamora, Pablo
A1 Swierkot, Jerzy
A1 den Broeder, Alfons A.
A1 De Vita, Salvatore
A1 Brix Petersen, Eva Rabing
A1 Li, Yang
A1 Ferrer, Miguel A.
A1 Escudero, Alejandro
A1 Netea, Mihai G.
A1 Coenen, Marieke J. H.
A1 Andersen, Vibeke
A1 Fonseca, Joao E.
A1 Jurado, Manuel
A1 Bogunia-Kubik, Katarzyna
A1 Collantes, Eduardo
A1 Sainz, Juan
K1 GWAS
K1 genetic variant
K1 rheumatoid arthritis
K1 drug response
K1 TNF inhibitors
K1 Tumor-necrosis-factor
K1 Genetic-variants
K1 Monoclonal-antibody
K1 Clinical register
K1 Soluble cd5
K1 Association
K1 Receptors
K1 Classification
K1 Polymorphisms
K1 Itolizumab
AB 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 (Delta DAS28). 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.
PB Frontiers media sa
SN 1664-3224
YR 2021
FD 2021-10-27
LK https://hdl.handle.net/10668/25696
UL https://hdl.handle.net/10668/25696
LA en
DS RISalud
RD Apr 17, 2025