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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

The Pharmacogenomics Journal volume 19, pages 83–96 (2019)Cite this article

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A Correction to this article was published on 14 February 2019

This article has been updated

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.

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Change history

  • 14 February 2019

    The original version of this Article contained an error in the spelling of the author Ana Rodríguez-Ramos, which was incorrectly given as Ana Rodríguez Ramos. This has now been corrected in both the PDF and HTML versions of the Article.

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Acknowledgements

We thank all participants who have agreed to participate in this study. We also thank María Dolores Casares, Ángeles Molina, and Carmen Oloriz for the collection of Spanish samples, and Hans Jurgen Hoffmann, Marianne Thomsen, Vibeke Østergaard Thomsen, Malene Rohr Andersen, Lise Lotte B. Laursen, Helle Jørgensen, Ram Benny Christian Dessau, Niels Steen Krogh, Ulla Vogel, Paal Skytt Andersen, Ivan Brandslund, Steffen Bank, Frederik Trier Møller, Nikolai Toft, and Niels Møller Andersen for the participation in collection and purification of Danish samples.

Funding:

This work was supported by grants from FIBAO foundation (Granada, Spain), Novo Nordisk Fonden (NNF15OC0016932), Knud og Edith Eriksens Mindefond and Gigtforeningen (A2037, A3570).

Author’s contributions:

RC and JS designed the study and drafted the manuscript. LMC, ARR, JMSM, and CBL were responsible for genotyping. MM-B, FC, and JS did the statistical data analysis. HC, AE, JSC, SS, MLH, MJSP, MAF, AG, BG, IF, EPP, AGU, MALN, PCZ, AdB, SdV, SEHJ, ECE, LQ, JEF, MJHC, VA, and JS coordinated the sample collection. HC, IF, and MJSP were involved in the records review and data acquisition. All authors contributed to, seen, and approved the final version of the manuscript.

Author information

Authors and Affiliations

  1. Genomic Oncology Area, GENYO Centre for Genomics and Oncological Research, Pfizer / University of Granada / Andalusian Regional Government, PTS Granada, Granada, Spain

    Luz M. Canet, Jose M. Sánchez-Maldonado, Rafael Cáliz, Ana Rodríguez-Ramos, Carmen B. Lupiañez, Juana Segura-Catena & Juan Sainz

  2. Rheumatology Department, Virgen de las Nieves University Hospital, Granada, Spain

    Rafael Cáliz, María José Soto-Pino, Miguel A. Ferrer, Antonio García, Alfonso González-Utrilla & Juan Sainz

  3. CEDOC, EpiDoC Unit, NOVA Medical School and National School of Public Health, Universidade Nova de Lisboa, Lisbon, Portugal

    Helena Canhão

  4. Area of Genomic Medicine, GENYO Centre for Genomics and Oncological Research, Pfizer / University of Granada / Andalusian Regional Government, Granada, Spain

    Manuel Martínez-Bueno

  5. Rheumatology Department, Reina Sofía Hospital/IMIBIC/University of Córdoba, Córdoba, Spain

    Alejandro Escudero & Eduardo Collantes-Estevez

  6. The Danish Rheumatologic Biobank, the DANBIO Registry and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Glostrup, Denmark

    Signe B Sorensen, Merete L Hetland, Bente Glintborg & Sven Erik Hobe Jacobsen

  7. Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Signe B Sorensen, Merete L Hetland & Sven Erik Hobe Jacobsen

  8. Department of Rheumatology, Gentofte and Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark

    Bente Glintborg

  9. Rheumatology Department, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca, Romania

    Ileana Filipescu

  10. Rheumatology Unit, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain

    Eva Pérez-Pampin

  11. Immunology Department, Virgen de las Nieves University Hospital, Granada, Spain

    Miguel Ángel López Nevot

  12. Clinical Analysis Department, Santa Lucía University Hospital, Cartagena, Spain

    Pablo Conesa-Zamora

  13. Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands

    Alfons den Broeder & Marieke J. H. Coenen

  14. Department of Medical and Biological Sciences, Clinic of Rheumatology, University of Udine, Udine, Italy

    Salvatore De Vita & Luca Quartuccio

  15. Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Federico Canzian

  16. Rheumatology and Metabolic Bone Diseases Department, Hospital de Santa Maria, CHLN, Lisbon, Portugal

    João E. Fonseca

  17. Rheumatology Research Unit, Faculty of Medicine, Instituto de Medicina Molecular, University of Lisbon, Lisbon Academic Medical Center, Lisbon, Portugal

    João E. Fonseca

  18. Focused Research Unit for Molecular Diagnostic and Clinical Research, IRS-Center Sonderjylland, Hospital of Southern Jutland, DK-6200, Aabenraa, Denmark

    Vibeke Andersen

  19. Faculty of Health Sciences, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Vibeke Andersen

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  1. Luz M. Canet
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Correspondence to Juan Sainz.

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VA has received compensation for consultancy and for being a member of an advisory board from MSD (Merck) and Janssen. All other authors declare that they have no competing financial interests.

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Canet, L.M., Sánchez-Maldonado, J.M., Cáliz, R. et al. Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients. Pharmacogenomics J 19, 83–96 (2019). https://doi.org/10.1038/s41397-018-0057-x

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