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Pharmacogenomics J. 2019 Feb;19(1):83-96. doi: 10.1038/s41397-018-0057-x. Epub 2018 Oct 5.

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

Author information

1
Genomic Oncology Area, GENYO Centre for Genomics and Oncological Research, Pfizer / University of Granada / Andalusian Regional Government, PTS Granada, Granada, Spain.
2
Rheumatology Department, Virgen de las Nieves University Hospital, Granada, Spain.
3
CEDOC, EpiDoC Unit, NOVA Medical School and National School of Public Health, Universidade Nova de Lisboa, Lisbon, Portugal.
4
Area of Genomic Medicine, GENYO Centre for Genomics and Oncological Research, Pfizer / University of Granada / Andalusian Regional Government, Granada, Spain.
5
Rheumatology Department, Reina Sofía Hospital/IMIBIC/University of Córdoba, Córdoba, Spain.
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.
7
Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
8
Department of Rheumatology, Gentofte and Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
9
Rheumatology Department, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania.
10
Rheumatology Unit, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain.
11
Immunology Department, Virgen de las Nieves University Hospital, Granada, Spain.
12
Clinical Analysis Department, Santa Lucía University Hospital, Cartagena, Spain.
13
Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
14
Department of Medical and Biological Sciences, Clinic of Rheumatology, University of Udine, Udine, Italy.
15
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
16
Rheumatology and Metabolic Bone Diseases Department, Hospital de Santa Maria, CHLN, Lisbon, Portugal.
17
Rheumatology Research Unit, Faculty of Medicine, Instituto de Medicina Molecular, University of Lisbon, Lisbon Academic Medical Center, Lisbon, Portugal.
18
Focused Research Unit for Molecular Diagnostic and Clinical Research, IRS-Center Sonderjylland, Hospital of Southern Jutland, DK-6200, Aabenraa, Denmark.
19
Faculty of Health Sciences, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
20
Genomic Oncology Area, GENYO Centre for Genomics and Oncological Research, Pfizer / University of Granada / Andalusian Regional Government, PTS Granada, Granada, Spain. juan.sainz@genyo.es.
21
Rheumatology Department, Virgen de las Nieves University Hospital, Granada, Spain. juan.sainz@genyo.es.

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.

PMID:
30287909
DOI:
10.1038/s41397-018-0057-x
[Indexed for MEDLINE]

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