Format

Send to

Choose Destination
Ann Rheum Dis. 2019 Aug;78(8):1055-1061. doi: 10.1136/annrheumdis-2018-214877. Epub 2019 Apr 29.

Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39.

Author information

1
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK A.Spiliopoulou@ed.ac.uk Paul.McKeigue@ed.ac.uk.
2
MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
3
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
4
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
5
NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
6
Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
7
Department of Human Genetics, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
8
Department of Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan.
9
The Centers of Research Excellence in Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
10
Department of Rheumatology, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
11
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
12
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
13
Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
14
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
15
Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
16
Amsterdam Rheumatology and Immunology Centre, Reade, Amsterdam, The Netherlands.
17
Department of Rheumatology, VU University Medical Centre, Amsterdam University Medical Centres, Amsterdam, The Netherlands.
18
Department of Clinical Immunology and Rheumatology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
19
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
20
CEDOC, EpiDoC Unit, NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal.
21
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
22
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
23
Rosalind Russell / Ephraim P Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, California, USA.
24
Center for Data Sciences, Harvard Medical School, Boston, Massachusetts, USA.
25
EULAR Centre of Excellence/UCD Centre for Arthritis Research, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
26
y Université Paris-Sud, INSERM UMR1184, Hôpitaux Universitaire Paris-Sud, AP-HP, Le Kremlin Bicêtre, Paris, France.
27
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
28
Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
29
School of Medicine, University of Leeds, Leeds, UK.
30
NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
31
Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK.

Abstract

OBJECTIVES:

We sought to investigate whether genetic effects on response to TNF inhibitors (TNFi) in rheumatoid arthritis (RA) could be localised by considering known genetic susceptibility loci for relevant traits and to evaluate the usefulness of these genetic loci for stratifying drug response.

METHODS:

We studied the relation of TNFi response, quantified by change in swollen joint counts ( Δ SJC) and erythrocyte sedimentation rate ( Δ ESR) with locus-specific scores constructed from genome-wide assocation study summary statistics in 2938 genotyped individuals: 37 scores for RA; scores for 19 immune cell traits; scores for expression or methylation of 93 genes with previously reported associations between transcript level and drug response. Multivariate associations were evaluated in penalised regression models by cross-validation.

RESULTS:

We detected a statistically significant association between Δ SJC and the RA score at the CD40 locus (p=0.0004) and an inverse association between Δ SJC and the score for expression of CD39 on CD4 T cells (p=0.00005). A previously reported association between CD39 expression on regulatory T cells and response to methotrexate was in the opposite direction. In stratified analysis by concomitant methotrexate treatment, the inverse association was stronger in the combination therapy group and dissipated in the TNFi monotherapy group. Overall, ability to predict TNFi response from genotypic scores was limited, with models explaining less than 1% of phenotypic variance.

CONCLUSIONS:

The association with the CD39 trait is difficult to interpret because patients with RA are often prescribed TNFi after failing to respond to methotrexate. The CD39 and CD40 pathways could be relevant for targeting drug therapy.

KEYWORDS:

anti-tnf; pharmacogenetics; rheumatoid arthritis

PMID:
31036624
DOI:
10.1136/annrheumdis-2018-214877
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center