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

John C. Taylor; T Bongartz; J Massey; B Mifsud; A Spiliopoulou; Ian C. Scott; Jianmei Wang; M Morgan; D Plant; M Colombo; P Orchard; Sarah Twigg; IB McInnes; Duncan  Porter; Jane E. Freeston; Jackie L. Nam; Heather J Cordell; John D. Isaacs; Jenna L. Strathdee; Donna K. Arnett; Maria J. H.  de Hair; Paul P Tak; Stella Aslibekyan; Ronald F. van Vollenhoven; Leonid Padyukov; S. Louis Bridges; Constantino Pitzalis; Andrew Cope; Suzanne M. Verstappen; Paul Emery; Michael R.  Barnes; Felix Agakov; Paul M. McKeigue; Taisei Mushiroda; Michiaki Kubo; Richard Weinshilboum; Anne Barton; Ann W Morgan; Jennifer H Barrett; on behalf of the MATURA, and PAMERA Consortia

doi:10.1038/s41397-018-0025-5

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

John C. Taylor, T Bongartz, J Massey, B Mifsud, A Spiliopoulou, Ian C. Scott, Jianmei Wang, M Morgan, D Plant, M Colombo, P Orchard, Sarah Twigg, IB McInnes, Duncan Porter, Jane E. Freeston, Jackie L. Nam, Heather J Cordell, John D. Isaacs, Jenna L. Strathdee, Donna K. ArnettMaria J. H. de Hair, Paul P Tak, Stella Aslibekyan, Ronald F. van Vollenhoven, Leonid Padyukov, S. Louis Bridges, Constantino Pitzalis, Andrew Cope, Suzanne M. Verstappen, Paul Emery, Michael R. Barnes, Felix Agakov, Paul M. McKeigue, Taisei Mushiroda, Michiaki Kubo, Richard Weinshilboum, Anne Barton, Ann W Morgan^* (Corresponding Author), Jennifer H Barrett, on behalf of the MATURA, and PAMERA Consortia

^*Corresponding author for this work

Medical Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	528-538
Number of pages	11
Journal	The Pharmacogenomics Journal
Volume	18
Early online date	25 May 2018
DOIs	https://doi.org/10.1038/s41397-018-0025-5
Publication status	Published - Jul 2018

Bibliographical note

We thank all the patients who have contributed to
this research, clinical staff who supported patient recruitment and
laboratory staff who undertook sample processing. We thank the
Medical Research Council (MRC) and Arthritis Research UK (ARUK)
for their joint funding of PEAC and MATURA (grant codes 36661 and
MR/K015346/1 and 20670 & 20022 (Experimental Arthritis Treatment Centre), respectively). The RAMS cohort was part funded by
ARUK (grant code 20385) and the National Institute for Health Research (NIHR) Manchester Musculoskeletal Biomedical Research
Unit (BRU). The YEAR and IACON studies were part funded by
program grants from ARUK (grant codes 18475 and 18387), the NIHR
Leeds Musculoskeletal BRU and Diagnostic Evaluation Co-operative,
the British Medical Association (Doris Hillier Award) and the Ann
Wilks Charitable Foundation. The IDEA study was supported by a
research grant from Investigator-Initiated Studies Program of Merck
Sharp & Dohme Limited. The opinions expressed in this paper are
those of the authors and do not necessarily represent those of Merck
Sharp & Dohme Limited. Pfizer provided study drug and unrestricted
grant funding for the EMPIRE study. The authors had the sole
responsibility for data analysis and manuscript preparation. ARUK
paid for the genotyping of CARDERA-1 and 2 (grant reference
19739). The SERA cohort was funded by Pfizer and the Scottish
Government (ETM40), and the SERA genomic analysis was funded
by the Stratified Medicine Scotland Innovation Centre (SMS-IC007).
Research in the Newcastle University Musculoskeletal Research
Group is supported by the National Institute for Health Research
Newcastle Biomedical Research Centre based at Newcastle Hospitals
NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the
NIHR or the Department of Health. I.C.S. and ST held Academic
Clinical Lectureships funded by the NIHR. This article presents
independent research partly funded by the NIHR. The views expressed
are those of the authors and not necessarily those of the NHS, the
NIHR or the Department of Health. The funders had no role in the
study design, data collection and analysis, data interpretation, the
writing of the manuscript or the decision to submit the manuscript for
publication. B.M. holds an MRC eMedLab Medical Bioinformatics
Career Development Fellowship, funded from award MR/L016311/1.
Part of this project was enabled through access to the MRC eMedLab
Medical Bioinformatics infrastructure (grant code MR/L016311/1) and
the MRC Leeds Medical Bioinformatics infrastructure (grant code
MR/L01629X/1). PAMERA was supported by the US NIH Pharmacogenomics Research Network (PGRN) funded by NIGMS (U19
GM61388) and the RIKEN Center for Integrative Medical Sciences. It
was funded in part by the Biobank Japan Project, funded by the
Ministry of Education, Culture, Sports, Science and Technology of
Japan. Acquisition and analysis of genetic and treatment response data
from the TEAR Trial were supported in part by NIH R01 AR052658
(SLB, Jr., PI) Predictors of Treatment Response in Early Aggressive
RA. The Synoviomics study was supported by the Dutch Arthritis
Foundation (grant NR06/1/303

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Taylor, J. C., Bongartz, T., Massey, J., Mifsud, B., Spiliopoulou, A., Scott, I. C., Wang, J., Morgan, M., Plant, D., Colombo, M., Orchard, P., Twigg, S., McInnes, IB., Porter, D., Freeston, J. E., Nam, J. L., Cordell, H. J., Isaacs, J. D., Strathdee, J. L., ... on behalf of the MATURA, and PAMERA Consortia (2018). Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients. The Pharmacogenomics Journal, 18, 528-538. https://doi.org/10.1038/s41397-018-0025-5

Taylor, JC, Bongartz, T, Massey, J, Mifsud, B, Spiliopoulou, A, Scott, IC, Wang, J, Morgan, M, Plant, D, Colombo, M, Orchard, P, Twigg, S, McInnes, IB, Porter, D, Freeston, JE, Nam, JL, Cordell, HJ, Isaacs, JD, Strathdee, JL, Arnett, DK, de Hair, MJH, Tak, PP, Aslibekyan, S, van Vollenhoven, RF, Padyukov, L, Bridges, SL, Pitzalis, C, Cope, A, Verstappen, SM, Emery, P, Barnes, MR, Agakov, F, McKeigue, PM, Mushiroda, T, Kubo, M, Weinshilboum, R, Barton, A, Morgan, AW, Barrett, JH & on behalf of the MATURA, and PAMERA Consortia 2018, 'Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients.', The Pharmacogenomics Journal, vol. 18, pp. 528-538. https://doi.org/10.1038/s41397-018-0025-5

@article{f4954c224266490598d099bfb37d73a8,

title = "Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients.",

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.",

author = "Taylor, {John C.} and T Bongartz and J Massey and B Mifsud and A Spiliopoulou and Scott, {Ian C.} and Jianmei Wang and M Morgan and D Plant and M Colombo and P Orchard and Sarah Twigg and IB McInnes and Duncan Porter and Freeston, {Jane E.} and Nam, {Jackie L.} and Cordell, {Heather J} and Isaacs, {John D.} and Strathdee, {Jenna L.} and Arnett, {Donna K.} and {de Hair}, {Maria J. H.} and Tak, {Paul P} and Stella Aslibekyan and {van Vollenhoven}, {Ronald F.} and Leonid Padyukov and Bridges, {S. Louis} and Constantino Pitzalis and Andrew Cope and Verstappen, {Suzanne M.} and Paul Emery and Barnes, {Michael R.} and Felix Agakov and McKeigue, {Paul M.} and Taisei Mushiroda and Michiaki Kubo and Richard Weinshilboum and Anne Barton and Morgan, {Ann W} and Barrett, {Jennifer H} and {on behalf of the MATURA, and PAMERA Consortia}",

note = "We thank all the patients who have contributed to this research, clinical staff who supported patient recruitment and laboratory staff who undertook sample processing. We thank the Medical Research Council (MRC) and Arthritis Research UK (ARUK) for their joint funding of PEAC and MATURA (grant codes 36661 and MR/K015346/1 and 20670 & 20022 (Experimental Arthritis Treatment Centre), respectively). The RAMS cohort was part funded by ARUK (grant code 20385) and the National Institute for Health Research (NIHR) Manchester Musculoskeletal Biomedical Research Unit (BRU). The YEAR and IACON studies were part funded by program grants from ARUK (grant codes 18475 and 18387), the NIHR Leeds Musculoskeletal BRU and Diagnostic Evaluation Co-operative, the British Medical Association (Doris Hillier Award) and the Ann Wilks Charitable Foundation. The IDEA study was supported by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Limited. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Limited. Pfizer provided study drug and unrestricted grant funding for the EMPIRE study. The authors had the sole responsibility for data analysis and manuscript preparation. ARUK paid for the genotyping of CARDERA-1 and 2 (grant reference 19739). The SERA cohort was funded by Pfizer and the Scottish Government (ETM40), and the SERA genomic analysis was funded by the Stratified Medicine Scotland Innovation Centre (SMS-IC007). Research in the Newcastle University Musculoskeletal Research Group is supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. I.C.S. and ST held Academic Clinical Lectureships funded by the NIHR. This article presents independent research partly funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in the study design, data collection and analysis, data interpretation, the writing of the manuscript or the decision to submit the manuscript for publication. B.M. holds an MRC eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. Part of this project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure (grant code MR/L016311/1) and the MRC Leeds Medical Bioinformatics infrastructure (grant code MR/L01629X/1). PAMERA was supported by the US NIH Pharmacogenomics Research Network (PGRN) funded by NIGMS (U19 GM61388) and the RIKEN Center for Integrative Medical Sciences. It was funded in part by the Biobank Japan Project, funded by the Ministry of Education, Culture, Sports, Science and Technology of Japan. Acquisition and analysis of genetic and treatment response data from the TEAR Trial were supported in part by NIH R01 AR052658 (SLB, Jr., PI) Predictors of Treatment Response in Early Aggressive RA. The Synoviomics study was supported by the Dutch Arthritis Foundation (grant NR06/1/303",

year = "2018",

month = jul,

doi = "10.1038/s41397-018-0025-5",

language = "English",

volume = "18",

pages = "528--538",

journal = "The Pharmacogenomics Journal",

issn = "1470-269X",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients.

AU - Taylor, John C.

AU - Bongartz, T

AU - Massey, J

AU - Mifsud, B

AU - Spiliopoulou, A

AU - Scott, Ian C.

AU - Wang, Jianmei

AU - Morgan, M

AU - Plant, D

AU - Colombo, M

AU - Orchard, P

AU - Twigg, Sarah

AU - McInnes, IB

AU - Porter, Duncan

AU - Freeston, Jane E.

AU - Nam, Jackie L.

AU - Cordell, Heather J

AU - Isaacs, John D.

AU - Strathdee, Jenna L.

AU - Arnett, Donna K.

AU - de Hair, Maria J. H.

AU - Tak, Paul P

AU - Aslibekyan, Stella

AU - van Vollenhoven, Ronald F.

AU - Padyukov, Leonid

AU - Bridges, S. Louis

AU - Pitzalis, Constantino

AU - Cope, Andrew

AU - Verstappen, Suzanne M.

AU - Emery, Paul

AU - Barnes, Michael R.

AU - Agakov, Felix

AU - McKeigue, Paul M.

AU - Mushiroda, Taisei

AU - Kubo, Michiaki

AU - Weinshilboum, Richard

AU - Barton, Anne

AU - Morgan, Ann W

AU - Barrett, Jennifer H

AU - on behalf of the MATURA, and PAMERA Consortia

N1 - We thank all the patients who have contributed to this research, clinical staff who supported patient recruitment and laboratory staff who undertook sample processing. We thank the Medical Research Council (MRC) and Arthritis Research UK (ARUK) for their joint funding of PEAC and MATURA (grant codes 36661 and MR/K015346/1 and 20670 & 20022 (Experimental Arthritis Treatment Centre), respectively). The RAMS cohort was part funded by ARUK (grant code 20385) and the National Institute for Health Research (NIHR) Manchester Musculoskeletal Biomedical Research Unit (BRU). The YEAR and IACON studies were part funded by program grants from ARUK (grant codes 18475 and 18387), the NIHR Leeds Musculoskeletal BRU and Diagnostic Evaluation Co-operative, the British Medical Association (Doris Hillier Award) and the Ann Wilks Charitable Foundation. The IDEA study was supported by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Limited. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Limited. Pfizer provided study drug and unrestricted grant funding for the EMPIRE study. The authors had the sole responsibility for data analysis and manuscript preparation. ARUK paid for the genotyping of CARDERA-1 and 2 (grant reference 19739). The SERA cohort was funded by Pfizer and the Scottish Government (ETM40), and the SERA genomic analysis was funded by the Stratified Medicine Scotland Innovation Centre (SMS-IC007). Research in the Newcastle University Musculoskeletal Research Group is supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. I.C.S. and ST held Academic Clinical Lectureships funded by the NIHR. This article presents independent research partly funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in the study design, data collection and analysis, data interpretation, the writing of the manuscript or the decision to submit the manuscript for publication. B.M. holds an MRC eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. Part of this project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure (grant code MR/L016311/1) and the MRC Leeds Medical Bioinformatics infrastructure (grant code MR/L01629X/1). PAMERA was supported by the US NIH Pharmacogenomics Research Network (PGRN) funded by NIGMS (U19 GM61388) and the RIKEN Center for Integrative Medical Sciences. It was funded in part by the Biobank Japan Project, funded by the Ministry of Education, Culture, Sports, Science and Technology of Japan. Acquisition and analysis of genetic and treatment response data from the TEAR Trial were supported in part by NIH R01 AR052658 (SLB, Jr., PI) Predictors of Treatment Response in Early Aggressive RA. The Synoviomics study was supported by the Dutch Arthritis Foundation (grant NR06/1/303

PY - 2018/7

Y1 - 2018/7

N2 - 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.

AB - 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.

UR - http://europepmc.org/abstract/med/29795407

U2 - 10.1038/s41397-018-0025-5

DO - 10.1038/s41397-018-0025-5

M3 - Article

C2 - 29795407

SN - 1470-269X

VL - 18

SP - 528

EP - 538

JO - The Pharmacogenomics Journal

JF - The Pharmacogenomics Journal

ER -

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

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