Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients
Canet, L. M.; Sanchez-Maldonado, J. M.; Caliz, R.; Rodriguez-Ramos, A.; Lupianez, C. B.; Canhao, H.; Martinez-Bueno, M.; Escudero, A.; Segura-Catena, J.; Sorensen, S. B.; Hetland, M. L.; Soto-Pino, M. J.; Ferrer, M. A.; Garcia, A.; Glintborg, B.; Filipescu, I.; Pérez Pampín, Eva; Gonzalez-Utrilla, A.; Nevot, M. A. L.; Conesa-Zamora, P.; den Broeder, A.; De Vita, S.; Jacobsen, S. E. H.; Collantes-Estevez, E.; Quartuccio, L.; Canzian, F.; Fonseca, J. E.; Coenen, M. J. H.; Andersen, V.; Sainz, J.
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Identificadores
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Fecha de publicación
2019Título de revista
PHARMACOGENOMICS JOURNAL
Tipo de contenido
Artigo
DeCS
ubicuitina-proteína ligasas | receptor de estrógenos beta | estudios de casos y controles | factor de necrosis tumoral alfa | humanos | haplotipos | antirreumáticos | hormonas esteroides gonadales | artritisMeSH
Tumor Necrosis Factor-alpha | Gonadal Steroid Hormones | Ubiquitin-Protein Ligases | Humans | Haplotypes | Antirheumatic Agents | Estrogen Receptor beta | Case-Control Studies | ArthritisResumen
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 x 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 x 10(-)(6) to P = 2.0 x 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.