RT Journal Article
T1 NFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors: Results from the REPAIR consortium.
A1 Sanchez-Maldonado, Jose Manuel
A1 Martinez-Bueno, Manuel
A1 Canhão, Helena
A1 Ter Horst, Rob
A1 Muñoz-Peña, Sonia
A1 Moñiz-Diez, Ana
A1 Rodriguez-Ramos, Ana
A1 Escudero, Alejandro
A1 Sorensen, Signe B
A1 Hetland, Merete L
A1 Ferrer, Miguel A
A1 Glintborg, Bente
A1 Filipescu, Ileana
A1 Perez-Pampin, Eva
A1 Conesa-Zamora, Pablo
A1 Garcia, Antonio
A1 den Broeder, Alfons
A1 De Vita, Salvatore
A1 Hove Jacobsen, Svend Erik
A1 Collantes, Eduardo
A1 Quartuccio, Luca
A1 Netea, Mihai G
A1 Li, Yang
A1 Fonseca, João E
A1 Jurado, Manuel
A1 Lopez-Nevot, Miguel Angel
A1 Coenen, Marieke J H
A1 Andersen, Vibeke
A1 Caliz, Rafael
A1 Sainz, Juan
K1 Arthritis, rheumatoid
K1 Biomarkers
K1 Case-control studies
K1 Female
K1 Follow-up studies
K1 Genetic predisposition to disease
AB This study sought to evaluate the association of 28 single nucleotide polymorphisms (SNPs) within NFKB and inflammasome pathway genes with the risk of rheumatoid arthritis (RA) and response to TNF inhibitors (TNFi). We conducted a case-control study in a European population of 1194 RA patients and 1328 healthy controls. The association of potentially interesting markers was validated with data from the DANBIO (695 RA patients and 978 healthy controls) and DREAM (882 RA patients) registries. The meta-analysis of our data with those from the DANBIO registry confirmed that anti-citrullinated protein antibodies (ACPA)-positive subjects carrying the NFKB2rs11574851T allele had a significantly increased risk of developing RA (PMeta_ACPA + = 0.0006) whereas no significant effect was found in ACPA-negative individuals (PMeta_ACPA- = 0.35). An ACPA-stratified haplotype analysis including both cohorts (n = 4210) confirmed that ACPA-positive subjects carrying the NFKB2TT haplotype had an increased risk of RA (OR = 1.39, P = 0.0042) whereas no effect was found in ACPA-negative subjects (OR = 1.04, P = 0.82). The meta-analysis of our data with those from the DANBIO and DREAM registries also revealed a suggestive association of the NFKB2rs1056890 SNP with larger changes in DAS28 (OR = 1.18, P = 0.007). Functional experiments showed that peripheral blood mononuclear cells from carriers of the NFKB2rs1005044C allele (in LD with the rs1056890, r2 = 1.00) showed increased production of IL10 after stimulation with LPS (P = 0.0026). These results provide first evidence of a role of the NFKB2 locus in modulating the risk of RA in an ACPA-dependent manner and suggest its implication in determining the response to TNFi. Additional studies are now warranted to further validate these findings.
PB Nature Publishing Group
YR 2020
FD 2020-02-07
LK http://hdl.handle.net/10668/15219
UL http://hdl.handle.net/10668/15219
LA en
NO Manuel Sánchez-Maldonado J, Martínez-Bueno M, Canhão H, Ter Horst R, Muñoz-Peña S, Moñiz-Díez A, et al. NFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors: Results from the REPAIR consortium. Sci Rep. 2020 Mar 9;10(1):4316
NO Tis work was partially supported by intramural funds of GENYO and FIBAO foundation (Granada, Spain); Novo Nordisk Fonden (NNF15OC0016932, VA);and Knud og Edith Eriksens Mindefond (VA) and Gigtforeningen (A2037, A3570, VA). MGN was supported by a Spinoza grant from the Netherlands Organization for Scientifc Research.
DS RISalud
RD Apr 10, 2025