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Investigation of genetically regulated gene expression and response to treatment in rheumatoid arthritis highlights an association between IL18RAP expression and treatment response.

Ann Rheum Dis. 2020 Nov;79(11):1446-1452. Epub 2020 Jul 30
Svetlana Cherlin 1 , Myles J Lewis 2 , Darren Plant 3 , Nisha Nair 4 , Katriona Goldmann 2 , Evan Tzanis 2 , Michael R Barnes 2 , Paul McKeigue 5 , Jennifer H Barrett 6 , Costantino Pitzalis 2 , Anne Barton 3 , MATURA Consortium , Heather J Cordell 7
Svetlana Cherlin 1 , Myles J Lewis 2 , Darren Plant 3 , Nisha Nair 4 , Katriona Goldmann 2 , Evan Tzanis 2 , Michael R Barnes 2 , Paul McKeigue 5 , Jennifer H Barrett 6 , Costantino Pitzalis 2 , Anne Barton 3 , MATURA Consortium , Heather J Cordell 7
+ et al

[No authors listed]

Author information
  • 1 Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK.
  • 2 Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • 3 NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
  • 4 Centre of Genetics & Genomics Versus Arthritis, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
  • 5 Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
  • 6 School of Medicine, University of Leeds, Leeds, UK.
  • 7 Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK heather.cordell@ncl.ac.uk.

摘要


OBJECTIVES:In this study, we sought to investigate whether there was any association between genetically regulated gene expression (as predicted using various reference panels) and anti-tumour necrosis factor (anti-TNF) treatment response (change in erythrocyte sedimentation rate (ESR)) using 3158 European ancestry patients with rheumatoid arthritis. METHODS:The genetically regulated portion of gene expression was estimated in the full cohort of 3158 subjects (as well as within a subcohort consisting of 1575 UK patients) using the PrediXcan software package with three different reference panels. Estimated expression was tested for association with anti-TNF treatment response. As a replication/validation experiment, we also investigated the correlation between change in ESR with measured gene expression at the Interleukin 18 Receptor Accessory Protein (IL18RAP) gene in whole blood and synovial tissue, using an independent replication data set of patients receiving conventional synthetic disease modifying anti-rheumatic drugs, with directly measured (via RNA sequencing) gene expression. RESULTS:We found that predicted expression of IL18RAP showed a consistent signal of association with treatment response across the reference panels. In our independent replication data set, IL18RAP expression in whole blood showed correlation with the change in ESR between baseline and follow-up (r=-0.35, p=0.0091). Change in ESR was also correlated with the expression of IL18RAP in synovial tissue (r=-0.28, p=0.02). CONCLUSION:Our results suggest that IL18RAP expression is worthy of further investigation as a potential predictor of treatment response in rheumatoid arthritis that is not specific to a particular drug type.

KEYWORDS: pharmacogenetics, rheumatoid arthritis, treatment