%0 Journal Article
%A Canet, Luz M
%A Sanchez-Maldonado, Jose M
%A Caliz, Rafael
%A Rodriguez-Ramos, Ana
%A Lupiañez, Carmen B
%A Canhão, Helena
%A Martinez-Bueno, Manuel
%A Escudero, Alejandro
%A Segura-Catena, Juana
%A Sorensen, Signe B
%A Hetland, Merete L
%A Soto-Pino, María Jose
%A Ferrer, Miguel A
%A Garcia, Antonio
%A Glintborg, Bente
%A Filipescu, Ileana
%A Perez-Pampin, Eva
%A Gonzalez-Utrilla, Alfonso
%A Nevot, Miguel Angel López
%A Conesa-Zamora, Pablo
%A Broeder, Alfons den
%A De Vita, Salvatore
%A Jacobsen, Sven Erik Hobe
%A Collantes-Estevez, Eduardo
%A Quartuccio, Luca
%A Canzian, Federico
%A Fonseca, João E
%A Coenen, Marieke J H
%A Andersen, Vibeke
%A Sainz, Juan
%T Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients.
%D 2018
%U http://hdl.handle.net/10668/13031
%X 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.
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