@misc{10481/71973,
year = {2021},
month = {10},
url = {http://hdl.handle.net/10481/71973},
abstract = {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
(DDAS28). 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 (perallele
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 metaanalysis
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.},
organization = {Instituto de Salud Carlos III	PI17/02276	
PI20/01845},
organization = {GENYO foundation (Granada, Spain)},
organization = {FIBAO foundation (Granada, Spain)},
organization = {Novo Nordisk Foundation	NNF15OC0016932},
organization = {Knud og Edith Eriksens Mindefond},
organization = {Gigtforeningen	A2037	
A3570},
organization = {National Science Centre, Poland	2016/21/B/NZ5/01901},
organization = {Spinoza grant from the Netherlands Organization for Scientific Research},
organization = {European Research Council (ERC)
European Commission	948207},
organization = {Radboud University Medical Centre Hypatia Grant (2018)},
publisher = {Frontiers Research Foundation},
keywords = {GWAS},
keywords = {Genetic variant},
keywords = {Rheumatoid arthritis},
keywords = {Drug response},
keywords = {TNF inhibitors},
title = {Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts},
doi = {10.3389/fimmu.2021.672255},
author = {Sánchez Maldonado, José Manuel and Cáliz Cáliz, Antonio Rafael and López Nevot, Miguel Ángel and Cabrera Serrano, Antonio José and Moñiz Díez, Ana and Ferrer Gamarra, Miguel Ángel and Jurado Chacón, Manuel and Sáinz Pérez, Juan},
}