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

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-ZamoraAlfons 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

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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
Pages (from-to)83-96
Number of pages9
JournalPharmacogenomics Journal
Volume19
Issue number1
Early online date5 Oct 2018
DOIs
Publication statusPublished - Feb 2019

Keywords

  • ESTROGEN REPLACEMENT THERAPY
  • SEX-HORMONES
  • T-LYMPHOCYTES
  • ALPHA
  • RISK
  • ASSOCIATION
  • EXPRESSION
  • DIFFERENTIATION
  • INDUCTION
  • PREGNANCY

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