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Genome-wide association study of response to tumour necrosis factor inhibitor therapy in rheumatoid arthritis

Lookup NU author(s): Professor John Isaacs

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Rheumatoid arthritis (RA) is characterised by chronic synovial joint inflammation. Treatment has been revolutionised by tumour necrosis factor alpha inhibitors (TNFi) but each available drug shows a significant non-response rate. We conducted a genome-wide association study of 1,752 UK RA TNFi-treated patients to identify predictors of change in the Disease Activity Score 28 (DAS28) and subcomponents over 3-6 months. The rs7195994 variant at the FTO gene locus was associated with infliximab response when looking at a change in the swollen joint count (SJC28) subcomponent (p = 9.74 x 10-9 ). Capture Hi-C data show chromatin interactions in GM12878 cells between rs2540767, in high linkage disequilibrium with rs7195994 (R2 =0.9) and IRX3, a neighbouring gene of FTO. IRX3 encodes a transcription factor involved in adipocyte remodelling and is regarded as the obesity gene at the FTO locus. Importantly, the rs7195994 association remained significantly associated following adjustment for BMI. In addition, using capture Hi-C data we showed interactions between TNFi-response associated variants and 16 RA susceptibility variants.


Publication metadata

Author(s): Massey J, Plant D, Hyrich K, Morgan AW, Wilson AG, Spiliopoulou A, Colombo M, McKeigue P, Isaacs J, Cordell H, Pitzalis C, Barton A

Publication type: Article

Publication status: Published

Journal: The Pharmacogenomics Journal

Year: 2018

Volume: 18

Issue: 5

Pages: 657-664

Print publication date: 01/09/2018

Online publication date: 31/08/2018

Acceptance date: 11/05/2018

Date deposited: 18/06/2018

ISSN (print): 1470-269X

ISSN (electronic): 1473-1150

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41397-018-0040-6

DOI: 10.1038/s41397-018-0040-6


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