Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients

John C Taylor¹, Tim Bongartz², Jonathan Massey^{3

4}, Borbala Mifsud⁵, Athina Spiliopoulou^{6

7}, Ian C Scott^{8

9}, Jianmei Wang¹⁰, Michael Morgan^{11

12}, Darren Plant^{3

4}, Marco Colombo⁶, Peter Orchard⁷, Sarah Twigg¹¹, Iain B McInnes¹³, Duncan Porter¹³, Jane E Freeston¹¹, Jackie L Nam¹¹, Heather J Cordell¹⁴, John D Isaacs¹⁵, Jenna L Strathdee¹, Donna Arnett¹⁶, Maria J H de Hair¹⁷, Paul P Tak^{18

19

20

21}, Stella Aslibekyan²², Ronald F van Vollenhoven²³, Leonid Padyukov²³, S Louis Bridges²², Costantino Pitzalis²⁴, Andrew P Cope²⁵, Suzanne M M Verstappen^{3

4}, Paul Emery¹¹, Michael R Barnes²⁴, Felix Agakov⁷, Paul McKeigue⁶, Taisei Mushiroda²⁶, Michiaki Kubo²⁶, Richard Weinshilboum²⁷, Anne Barton^{3

4}, Ann W Morgan²⁸, Jennifer H Barrett¹; MATURA; and PAMERA; Consortia

Affiliations

¹ Leeds Institute of Cancer and Pathology, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
² Vanderbilt University, Nashville, TN, USA.
³ Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
⁴ NIHR Manchester BRC, Central Manchester Foundation Trust, Manchester, UK.
⁵ Clinical Pharmacology, William Harvey Research Institute, Queen Mary University, London, UK.
⁶ Centre for Population Health Sciences, Usher Institute, University of Edinburgh Old Medical School, Teviot Place, Edinburgh, UK.
⁷ Pharmatics Ltd., 9, Little France Road, Edinburgh, UK.
⁸ Research Institute for Primary Care and Health Sciences, Primary Care Sciences, Keele University and Department of Rheumatology, Haywood Hospital, High Lane, Burslem, Staffordshire, UK.
⁹ Department of Medical and Molecular Genetics, King's College London, London, UK.
¹⁰ Roche Products, Welwyn Garden City, UK.
¹¹ Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
¹² Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK.
¹³ Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
¹⁴ Institute of Genetic Medicine, Newcastle University, Newcastle, UK.
¹⁵ Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University and NIHR Newcastle Biomedical Research Centre in Ageing and Long Term Conditions, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
¹⁶ University of Kentucky College of Public Health, Lexington, KY, 40536, USA.
¹⁷ University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁸ Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
¹⁹ GlaxoSmithKline, Stevenage, UK.
²⁰ Cambridge University, Cambridge, UK.
²¹ Ghent University, Ghent, Belgium.
²² Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA.
²³ Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
²⁴ Barts and The London School of Medicine & Dentistry, William Harvey Research Institute, Queen Mary University, London, UK.
²⁵ Academic Department of Rheumatology, Faculty of Life Sciences and Medicine, King's College London, London, UK.
²⁶ RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
²⁷ Mayo Clinic, Rochester, MN, USA.
²⁸ Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK. a.w.morgan@leeds.ac.uk.

PMID: 29795407
DOI: 10.1038/s41397-018-0025-5

Free article

Review

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients

John C Taylor et al. Pharmacogenomics J. 2018 Jul.

Free article

. 2018 Jul;18(4):528-538.

doi: 10.1038/s41397-018-0025-5. Epub 2018 May 25.

Authors

Affiliations

¹ Leeds Institute of Cancer and Pathology, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
² Vanderbilt University, Nashville, TN, USA.
³ Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
⁴ NIHR Manchester BRC, Central Manchester Foundation Trust, Manchester, UK.
⁵ Clinical Pharmacology, William Harvey Research Institute, Queen Mary University, London, UK.
⁶ Centre for Population Health Sciences, Usher Institute, University of Edinburgh Old Medical School, Teviot Place, Edinburgh, UK.
⁷ Pharmatics Ltd., 9, Little France Road, Edinburgh, UK.
⁸ Research Institute for Primary Care and Health Sciences, Primary Care Sciences, Keele University and Department of Rheumatology, Haywood Hospital, High Lane, Burslem, Staffordshire, UK.
⁹ Department of Medical and Molecular Genetics, King's College London, London, UK.
¹⁰ Roche Products, Welwyn Garden City, UK.
¹¹ Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
¹² Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK.
¹³ Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
¹⁴ Institute of Genetic Medicine, Newcastle University, Newcastle, UK.
¹⁵ Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University and NIHR Newcastle Biomedical Research Centre in Ageing and Long Term Conditions, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
¹⁶ University of Kentucky College of Public Health, Lexington, KY, 40536, USA.
¹⁷ University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁸ Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
¹⁹ GlaxoSmithKline, Stevenage, UK.
²⁰ Cambridge University, Cambridge, UK.
²¹ Ghent University, Ghent, Belgium.
²² Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA.
²³ Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
²⁴ Barts and The London School of Medicine & Dentistry, William Harvey Research Institute, Queen Mary University, London, UK.
²⁵ Academic Department of Rheumatology, Faculty of Life Sciences and Medicine, King's College London, London, UK.
²⁶ RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
²⁷ Mayo Clinic, Rochester, MN, USA.
²⁸ Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK. a.w.morgan@leeds.ac.uk.

PMID: 29795407
DOI: 10.1038/s41397-018-0025-5

Abstract

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10^-7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

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Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients

Affiliations

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients

Authors

Affiliations

Abstract

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LinkOut - more resources

Full Text Sources

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Medical

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