Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases

J. Cobb; E. Cule; H. Moncrieffe; A. Hinks; S. Ursu; F. Patrick; L. Kassoumeri; E. Flynn; M. Bulatović; N. Wulffraat; B. Van Zelst; R. De Jonge; M. Bohm; P. Dolezalova; S. Hirani; S. Newman; P. Whitworth; T. R. Southwood; M. De Iorio; L. R. Wedderburn; W. Thomson

doi:10.1038/tpj.2014.3

Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases

J. Cobb^*, E. Cule, H. Moncrieffe, A. Hinks, S. Ursu, F. Patrick, L. Kassoumeri, E. Flynn, M. Bulatović, N. Wulffraat, B. Van Zelst, R. De Jonge, M. Bohm, P. Dolezalova, S. Hirani, S. Newman, P. Whitworth, T. R. Southwood, M. De Iorio, L. R. WedderburnW. Thomson

^*Corresponding author for this work

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

Abstract

Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to a targeted treatment. We genotyped 759 JIA cases from the UK, the Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of the treatment. In Phase I analysis, samples were analysed for the association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P<1 × 10 -5): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help to reach our goal of predicting response to MTX in JIA.

Original language	English
Pages (from-to)	356-364
Number of pages	9
Journal	Pharmacogenomics Journal
Volume	14
Issue number	4
DOIs	https://doi.org/10.1038/tpj.2014.3
Publication status	Published - Aug 2014

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Cobb, J., Cule, E., Moncrieffe, H., Hinks, A., Ursu, S., Patrick, F., Kassoumeri, L., Flynn, E., Bulatović, M., Wulffraat, N., Van Zelst, B., De Jonge, R., Bohm, M., Dolezalova, P., Hirani, S., Newman, S., Whitworth, P., Southwood, T. R., De Iorio, M., ... Thomson, W. (2014). Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases. Pharmacogenomics Journal, 14(4), 356-364. https://doi.org/10.1038/tpj.2014.3

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title = "Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases",

abstract = "Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to a targeted treatment. We genotyped 759 JIA cases from the UK, the Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of the treatment. In Phase I analysis, samples were analysed for the association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P<1 × 10 -5): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help to reach our goal of predicting response to MTX in JIA.",

keywords = "juvenile idiopathic arthritis, methotrexate, pharmacogenetics, response",

author = "J. Cobb and E. Cule and H. Moncrieffe and A. Hinks and S. Ursu and F. Patrick and L. Kassoumeri and E. Flynn and M. Bulatovi{\'c} and N. Wulffraat and {Van Zelst}, B. and {De Jonge}, R. and M. Bohm and P. Dolezalova and S. Hirani and S. Newman and P. Whitworth and Southwood, {T. R.} and {De Iorio}, M. and Wedderburn, {L. R.} and W. Thomson",

year = "2014",

month = aug,

doi = "10.1038/tpj.2014.3",

language = "English",

volume = "14",

pages = "356--364",

journal = "Pharmacogenomics Journal",

issn = "1470-269X",

publisher = "Nature Publishing Group",

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Cobb, J, Cule, E, Moncrieffe, H, Hinks, A, Ursu, S, Patrick, F, Kassoumeri, L, Flynn, E, Bulatović, M, Wulffraat, N, Van Zelst, B, De Jonge, R, Bohm, M, Dolezalova, P, Hirani, S, Newman, S, Whitworth, P, Southwood, TR, De Iorio, M, Wedderburn, LR & Thomson, W 2014, 'Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases', Pharmacogenomics Journal, vol. 14, no. 4, pp. 356-364. https://doi.org/10.1038/tpj.2014.3

TY - JOUR

T1 - Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases

AU - Cobb, J.

AU - Cule, E.

AU - Moncrieffe, H.

AU - Hinks, A.

AU - Ursu, S.

AU - Patrick, F.

AU - Kassoumeri, L.

AU - Flynn, E.

AU - Bulatović, M.

AU - Wulffraat, N.

AU - Van Zelst, B.

AU - De Jonge, R.

AU - Bohm, M.

AU - Dolezalova, P.

AU - Hirani, S.

AU - Newman, S.

AU - Whitworth, P.

AU - Southwood, T. R.

AU - De Iorio, M.

AU - Wedderburn, L. R.

AU - Thomson, W.

PY - 2014/8

Y1 - 2014/8

N2 - Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to a targeted treatment. We genotyped 759 JIA cases from the UK, the Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of the treatment. In Phase I analysis, samples were analysed for the association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P<1 × 10 -5): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help to reach our goal of predicting response to MTX in JIA.

AB - Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to a targeted treatment. We genotyped 759 JIA cases from the UK, the Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of the treatment. In Phase I analysis, samples were analysed for the association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P<1 × 10 -5): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help to reach our goal of predicting response to MTX in JIA.

KW - juvenile idiopathic arthritis

KW - methotrexate

KW - pharmacogenetics

KW - response

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SN - 1470-269X

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SP - 356

EP - 364

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

IS - 4

ER -

Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases

Abstract

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