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

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Massey J1, Plant D2, Hyrich K2,3, Morgan AW4, Wilson AG5, Spiliopoulou A6,7, Colombo M6, McKeigue P6, Isaacs J8, Cordell H9, Pitzalis C10, Barton A11,12; BRAGGSS, MATURA Consortium. Pharmacogenomics J. 2018 Sep;18(5):657-664. doi: 10.1038/s41397-018-0040-6. Epub 2018 Aug 31.

Abstract

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1 Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.

2 NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

3 Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.

4 School of Medicine, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

5 School of Medicine & Medical Science, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.

6 Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, UK.

7 Pharmatics Ltd, 9 Little France Rd, Edinburgh, UK.

8 Institute of Cellular Medicine, Newcastle University, and NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

9 Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

10 William Harvey Research Institute, Barts and The London School of Medicine & Dentistry and Barts Health NHS, Queen Mary University of London, London, UK.

11 Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK. anne.barton@manchester.ac.uk.

12 NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. anne.barton@manchester.ac.uk.

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 1752 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 × 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.