Investigation of genetically-regulated gene expression and response to treatment in rheumatoid arthritis highlights an association between <em>IL18RAP </em>expression and treatment response

Cherlin, S; Lewis, MJ; Plant, D; Nair, N; Goldmann, K; Tzanis, E; Barnes, MR; McKeigue, P; Barrett, JH; Pitzalis, C; Barton, A; Cordell, HJ

doi:10.1136/annrheumdis-2020-217204

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

Lookup NU author(s): Dr Svetlana Cherlin ORCiD, Professor Heather Cordell

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Abstract

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-TNF treatment response (change in erythrocyte sedimentation rate, ESR) using 3,158 European ancestry rheumatoid arthritis patients. Methods The genetically-regulated portion of gene expression was estimated in the full cohort of 3,158 subjects (as well as within a sub-cohort consisting of 1,575 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.

Publication metadata

Author(s): Cherlin S, Lewis MJ, Plant D, Nair N, Goldmann K, Tzanis E, Barnes MR, McKeigue P, Barrett JH, Pitzalis C, Barton A, Cordell HJ

Publication type: Article

Publication status: Published

Journal: Annals of the Rheumatic Diseases

Year: 2020

Volume: 79

Issue: 11

Pages: 1446-1452

Print publication date: 01/11/2020

Online publication date: 30/07/2020

Acceptance date: 21/06/2020

Date deposited: 21/06/2020

ISSN (print): 0003-4967

ISSN (electronic): 1468-2060

Publisher: BMJ Group

URL: https://doi.org/10.1136/annrheumdis-2020-217204

DOI: 10.1136/annrheumdis-2020-217204

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Funding

Funder reference	Funder name
JHB receives support from the NIHR through the Leeds Biomedical Research Centre
MRC/Arthritis Research UK award: Maximizing Therapeutic Utility in RA (MATURA) (Grant MR-K015346)
Musculoskeletal theme of the NIHR Manchester BRC for their support.
Pathobiology of Early Arthritis Cohort (PEAC) was supported by funding from the Medical Research Council (MRC) (grant number G0800648).
We thank Arthritis Research UK (grant number 20385)
This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (grant number MR/L016311/1).
Wellcome Trust (Grant 102858/Z/13/Z)

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