TY - JOUR
T1 - NFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors
T2 - Results from the REPAIR consortium
AU - Manuel Sánchez-Maldonado, Jose
AU - Martínez-Bueno, Manuel
AU - Canhão, Helena
AU - ter Horst, Rob
AU - Muñoz-Peña, Sonia
AU - Moñiz-Díez, Ana
AU - Rodríguez-Ramos, Ana
AU - Escudero, Alejandro
AU - Sorensen, Signe B.
AU - Hetland, Merete L.
AU - Ferrer, Miguel A.
AU - Glintborg, Bente
AU - Filipescu, Ileana
AU - Pérez-Pampin, Eva
AU - Conesa-Zamora, Pablo
AU - García, Antonio
AU - den Broeder, Alfons
AU - De Vita, Salvatore
AU - Hove Jacobsen, Svend Erik
AU - Collantes, Eduardo
AU - Quartuccio, Luca
AU - Netea, Mihai G.
AU - Li, Yang
AU - Fonseca, João E.
AU - Jurado, Manuel
AU - López-Nevot, Miguel Ángel
AU - Coenen, Marieke J.H.
AU - Andersen, Vibeke
AU - Cáliz, Rafael
AU - Sainz, Juan
PY - 2020/3/9
Y1 - 2020/3/9
N2 - 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.
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.
U2 - 10.1038/s41598-020-61331-5
DO - 10.1038/s41598-020-61331-5
M3 - Journal article
C2 - 32152480
AN - SCOPUS:85081562854
SN - 2045-2322
VL - 10
JO - Scientific Reports
JF - Scientific Reports
M1 - 4316
ER -