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Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis
  1. Maša Umiċeviċ Mirkov1,
  2. Jing Cui2,
  3. Sita H Vermeulen1,3,
  4. Eli A Stahl2,
  5. Erik J M Toonen4,
  6. Remco R Makkinje1,
  7. Annette T Lee5,
  8. Tom W J Huizinga6,
  9. Renee Allaart6,
  10. Anne Barton7,8,
  11. Xavier Mariette9,
  12. Corinne Richard Miceli9,
  13. Lindsey A Criswell10,
  14. Paul P Tak11,12,
  15. Niek de Vries11,12,
  16. Saedis Saevarsdottir13,
  17. Leonid Padyukov13,
  18. S Louis Bridges14,
  19. Dirk-Jan van Schaardenburg15,16,
  20. Tim L Jansen17,
  21. Ellen A J Dutmer18,
  22. Mart A F J van de Laar19,
  23. Pilar Barrera17,
  24. Timothy R D J Radstake20,
  25. Piet L C M van Riel17,
  26. Hans Scheffer1,
  27. Barbara Franke1,21,
  28. Han G Brunner1,
  29. Robert M Plenge2,
  30. Peter K Gregersen5,
  31. Henk-Jan Guchelaar22,
  32. Marieke J H Coenen1
  1. 1Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  2. 2Department of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Broad Institute, Boston, Massachusetts, USA
  3. 3Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  4. 4Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  5. 5Robert S Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, North Shore -LIJ, Manhasset, New York, USA.
  6. 6Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  7. 7Arthritis Research UK Epidemiology Unit, Manchester Academy of Health Sciences, The University of Manchester, Manchester, UK
  8. 8NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
  9. 9Department of Rheumatology, Université Paris-Sud, AP-HP, Hôpitaux Universitaires Paris-Sud, INSERM U1012, Le Kremlin Bicêtre, Paris, France
  10. 10Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California, San Francisco, California, USA
  11. 11Department of Clinical Immunology and Rheumatology, AMC/University of Amsterdam, Amsterdam, The Netherlands
  12. 12GlaxoSmithKline, Stevenage, UK
  13. 13Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden
  14. 14Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, USA
  15. 15Department of Rheumatology, Reade Centre for Rehabilitation and Rheumatology (formerly Jan van Breemen Institute), Amsterdam, The Netherlands
  16. 16Department of Rheumatology, VU University Medical Centre, Amsterdam, The Netherlands
  17. 17Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  18. 18Department of Rheumatology, Gelderse Vallei Hospital, Ede, The Netherlands
  19. 19Department of Rheumatology and Clinical Immunology, Arthritis Center Twente, University Twente & Medisch Spectrum Twente, Enschede, The Netherlands
  20. 20Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht & Wilhemina Children's Hospital, Utrecht, The Netherlands
  21. 21Department of Psychiatry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  22. 22Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Dr Marieke Coenen, Department of Human Genetics (855), Nijmegen Centre for Evidence Based Practice and Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen 6500 HB, The Netherlands; m.coenen{at}gen.umcn.nl

Abstract

Background Treatment strategies blocking tumour necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently, there are no means of identifying these patients before treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patients with RA using a genome-wide association approach.

Methods We conducted a multistage, genome-wide association study with a primary analysis of 2 557 253 single-nucleotide polymorphisms (SNPs) in 882 patients with RA receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with p<10−3 were selected for replication in 1821 patients from three independent cohorts. Pathway analysis including all SNPs with p<10−3 was performed using Ingenuity.

Results 772 markers showed evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p value in the overall meta-analysis compared with the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four cohorts studied. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology.

Conclusions Using a multistage strategy, we have identified eight genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.

  • Anti-TNF
  • Gene Polymorphism
  • Pharmacogenetics
  • Rheumatoid Arthritis

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