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Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients

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  • Luz M Canet
  • Jose M Sánchez-Maldonado
  • Rafael Cáliz
  • Ana Rodríguez Ramos
  • Carmen B Lupiañez
  • Helena Canhão
  • Manuel Martínez-Bueno
  • Alejandro Escudero
  • Juana Segura-Catena
  • Signe B Sorensen
  • Merete L Hetland
  • María José Soto-Pino
  • Miguel A Ferrer
  • Antonio García
  • Bente Glintborg
  • Ileana Filipescu
  • Eva Pérez-Pampin
  • Alfonso González-Utrilla
  • Miguel Ángel López Nevot
  • Pablo Conesa-Zamora
  • Alfons den Broeder
  • Salvatore De Vita
  • Sven Erik Hobe Jacobsen
  • Eduardo Collantes-Estevez
  • Luca Quartuccio
  • Federico Canzian
  • João E Fonseca
  • Marieke J H Coenen
  • Vibeke Andersen
  • Juan Sainz
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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.

Original languageEnglish
JournalThe pharmacogenomics journal
Volume19
Issue number1
Pages (from-to)83-96
ISSN1470-269X
DOIs
Publication statusPublished - 2019

ID: 56070256