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

The Pharmacogenomics Journal
Jonathan MasseyBRAGGSS, MATURA Consortium

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.

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Citations

Oct 12, 2019·Nature Reviews. Rheumatology·Nisha Nair, Anthony G Wilson
Jun 13, 2019·Journal of Clinical Medicine·Marialbert Acosta-HerreraJavier Martín
Apr 16, 2020·Frontiers in Genetics·Xin FengFengfeng Zhou
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May 1, 2019·Annals of the Rheumatic Diseases·Athina SpiliopoulouPaul McKeigue
Jul 23, 2019·Rheumatology·Darren Plant, Anne Barton
Oct 12, 2019·Science·Eleftheria ZegginiLouise V Wain
Aug 31, 2020·Rheumatology·Bako NouriAnne Barton
Jul 9, 2020·Rheumatology·Laura E Dedmon
Mar 28, 2020·Pharmacogenomics and Personalized Medicine·Hyun Jeong KimKyung Eun Lee
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Feb 25, 2021·Expert Review of Clinical Immunology·Ikram MezghicheElisabetta Bianchi
Jun 22, 2021·Clinical Pharmacology and Therapeutics·Ayesha MuhammadSara L Van Driest

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Datasets Mentioned

BETA
GM12878

Methods Mentioned

BETA
genotyping
ESR
Hi-C
HiC
GTPase
Capture-HiC
Capture Hi-C

Software Mentioned

BRAGGSS
SNPTEST
SHAPEIT2
GCTA
R interface

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