RT Journal Article
T1 Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients.
A1 Canet, Luz M
A1 Sanchez-Maldonado, Jose M
A1 Caliz, Rafael
A1 Rodriguez-Ramos, Ana
A1 Lupiañez, Carmen B
A1 Canhão, Helena
A1 Martinez-Bueno, Manuel
A1 Escudero, Alejandro
A1 Segura-Catena, Juana
A1 Sorensen, Signe B
A1 Hetland, Merete L
A1 Soto-Pino, María Jose
A1 Ferrer, Miguel A
A1 Garcia, Antonio
A1 Glintborg, Bente
A1 Filipescu, Ileana
A1 Perez-Pampin, Eva
A1 Gonzalez-Utrilla, Alfonso
A1 Nevot, Miguel Angel López
A1 Conesa-Zamora, Pablo
A1 Broeder, Alfons den
A1 De Vita, Salvatore
A1 Jacobsen, Sven Erik Hobe
A1 Collantes-Estevez, Eduardo
A1 Quartuccio, Luca
A1 Canzian, Federico
A1 Fonseca, João E
A1 Coenen, Marieke J H
A1 Andersen, Vibeke
A1 Sainz, Juan
AB The aim of this case-control study was to evaluate whether 47 single-nucleotide polymorphisms (SNPs) in steroid hormone-related genes are associated with the risk of RA and anti-TNF drug response. We conducted a case-control study in 3 European populations including 2936 RA patients and 2197 healthy controls. Of those, a total of 1985 RA patients were treated with anti-TNF blockers. The association of potentially interesting markers in the discovery population was validated through meta-analysis with data from DREAM and DANBIO registries. Although none of the selected variants had a relevant role in modulating RA risk, the meta-analysis of the linear regression data with those from the DREAM and DANBIO registries showed a significant correlation of the CYP3A4rs11773597 and CYP2C9rs1799853 variants with changes in DAS28 after the administration of anti-TNF drugs (P = 0.00074 and P = 0.006, respectively). An overall haplotype analysis also showed that the ESR2GGG haplotype significantly associated with a reduced chance of having poor response to anti-TNF drugs (P = 0.0009). Finally, a ROC curve analysis confirmed that a model built with eight steroid hormone-related variants significantly improved the ability to predict drug response compared with the reference model including demographic and clinical variables (AUC = 0.633 vs. AUC = 0.556; PLR_test = 1.52 × 10-6). These data together with those reporting that the CYP3A4 and ESR2 SNPs correlate with the expression of TRIM4 and ESR2 mRNAs in PBMCs (ranging from P = 1.98 × 10-6 to P = 2.0 × 10-35), and that the CYP2C9rs1799853 SNP modulates the efficiency of multiple drugs, suggest that steroid hormone-related genes may have a role in determining the response to anti-TNF drugs.KEY POINTS• Polymorphisms within the CYP3A4 and CYP2C9 loci correlate with changes in DAS28 after treatment with anti-TNF drugs.• A haplotype including eQTL SNPs within the ESR2 gene associates with better response to anti-TNF drugs.• A genetic model built with eight steroid hormone-related variants significantly improved the ability to predict drug response.
PB Nature Publishing Group
YR 2018
FD 2018-08-10
LK http://hdl.handle.net/10668/13031
UL http://hdl.handle.net/10668/13031
LA en
DS RISalud
RD Apr 12, 2025