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

Athina Spiliopoulou; Marco Colombo; Darren Plant; Nisha Nair; Jing Cui; Radboudumc Coenen; Katsunori Ikari; Hisashi Yamanaka; Saedis Saevarsdottir; Leonid Padyukov; S Louis Bridges Jr.; Robert P Kimberly; Yukinori Okada; Piet L CM van Riel; Gertjan Wolbink; Irene E van der Horst-Bruinsma; Niek de Vries; Paul P Tak; Koichiro Ohmura; Helena Canhão; Henk-Jan Guchelaar; Tom WJ Huizinga; Lindsey A Criswell; Soumya Raychaudhuri; Michael E Weinblatt; Anthony G Wilson; Xavier Mariette; John D Isaacs; Ann W Morgan; Costantino Pitzalis; Anne Barton; Paul McKeigue

doi:10.1136/annrheumdis-2018-214877

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

Athina Spiliopoulou, Marco Colombo, Darren Plant, Nisha Nair, Jing Cui, Radboudumc Coenen, Katsunori Ikari, Hisashi Yamanaka, Saedis Saevarsdottir, Leonid Padyukov, S Louis Bridges Jr., Robert P Kimberly, Yukinori Okada, Piet L CM van Riel, Gertjan Wolbink, Irene E van der Horst-Bruinsma, Niek de Vries, Paul P Tak, Koichiro Ohmura, Helena CanhãoHenk-Jan Guchelaar, Tom WJ Huizinga, Lindsey A Criswell, Soumya Raychaudhuri, Michael E Weinblatt, Anthony G Wilson, Xavier Mariette, John D Isaacs, Ann W Morgan, Costantino Pitzalis, Anne Barton, Paul McKeigue

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Abstract / Description of output

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.

Original language	English
Pages (from-to)	1055-1061
Number of pages	7
Journal	Annals of the Rheumatic Diseases
Volume	78
Issue number	8
Early online date	29 Apr 2019
DOIs	https://doi.org/10.1136/annrheumdis-2018-214877
Publication status	Published - Aug 2019

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Association of response to TNF inhibitors...
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Paul McKeigue
- Deanery of Molecular, Genetic and Population Health Sciences - Chair of Genetic Epidemiology and Statistical Genetics
- Usher Institute
- Centre for Population Health Sciences
Person: Academic: Research Active

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Spiliopoulou, A., Colombo, M., Plant, D., Nair, N., Cui, J., Coenen, R., Ikari, K., Yamanaka, H., Saevarsdottir, S., Padyukov, L., Bridges Jr., S. L., Kimberly, R. P., Okada, Y., van Riel, P. L. CM., Wolbink, G., van der Horst-Bruinsma, I. E., de Vries, N., Tak, P. P., Ohmura, K., ... McKeigue, P. (2019). Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39. Annals of the Rheumatic Diseases, 78(8), 1055-1061. https://doi.org/10.1136/annrheumdis-2018-214877

@article{f46f5a3447e741d68629b10e7ec51a6e,

title = "Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39",

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.",

author = "Athina Spiliopoulou and Marco Colombo and Darren Plant and Nisha Nair and Jing Cui and Radboudumc Coenen and Katsunori Ikari and Hisashi Yamanaka and Saedis Saevarsdottir and Leonid Padyukov and {Bridges Jr.}, {S Louis} and Kimberly, {Robert P} and Yukinori Okada and {van Riel}, {Piet L CM} and Gertjan Wolbink and {van der Horst-Bruinsma}, {Irene E} and {de Vries}, Niek and Tak, {Paul P} and Koichiro Ohmura and Helena Canh{\~a}o and Henk-Jan Guchelaar and Huizinga, {Tom WJ} and Criswell, {Lindsey A} and Soumya Raychaudhuri and Weinblatt, {Michael E} and Wilson, {Anthony G} and Xavier Mariette and Isaacs, {John D} and Morgan, {Ann W} and Costantino Pitzalis and Anne Barton and Paul McKeigue",

note = "{\textcopyright} Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.",

year = "2019",

month = aug,

doi = "10.1136/annrheumdis-2018-214877",

language = "English",

volume = "78",

pages = "1055--1061",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "BMJ Publishing Group",

number = "8",

}

Spiliopoulou, A, Colombo, M, Plant, D, Nair, N, Cui, J, Coenen, R, Ikari, K, Yamanaka, H, Saevarsdottir, S, Padyukov, L, Bridges Jr., SL, Kimberly, RP, Okada, Y, van Riel, PLCM, Wolbink, G, van der Horst-Bruinsma, IE, de Vries, N, Tak, PP, Ohmura, K, Canhão, H, Guchelaar, H-J, Huizinga, TWJ, Criswell, LA, Raychaudhuri, S, Weinblatt, ME, Wilson, AG, Mariette, X, Isaacs, JD, Morgan, AW, Pitzalis, C, Barton, A & McKeigue, P 2019, 'Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39', Annals of the Rheumatic Diseases, vol. 78, no. 8, pp. 1055-1061. https://doi.org/10.1136/annrheumdis-2018-214877

TY - JOUR

T1 - Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39

AU - Spiliopoulou, Athina

AU - Colombo, Marco

AU - Plant, Darren

AU - Nair, Nisha

AU - Cui, Jing

AU - Coenen, Radboudumc

AU - Ikari, Katsunori

AU - Yamanaka, Hisashi

AU - Saevarsdottir, Saedis

AU - Padyukov, Leonid

AU - Bridges Jr., S Louis

AU - Kimberly, Robert P

AU - Okada, Yukinori

AU - van Riel, Piet L CM

AU - Wolbink, Gertjan

AU - van der Horst-Bruinsma, Irene E

AU - de Vries, Niek

AU - Tak, Paul P

AU - Ohmura, Koichiro

AU - Canhão, Helena

AU - Guchelaar, Henk-Jan

AU - Huizinga, Tom WJ

AU - Criswell, Lindsey A

AU - Raychaudhuri, Soumya

AU - Weinblatt, Michael E

AU - Wilson, Anthony G

AU - Mariette, Xavier

AU - Isaacs, John D

AU - Morgan, Ann W

AU - Pitzalis, Costantino

AU - Barton, Anne

AU - McKeigue, Paul

PY - 2019/8

Y1 - 2019/8

N2 - 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.

AB - 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.

U2 - 10.1136/annrheumdis-2018-214877

DO - 10.1136/annrheumdis-2018-214877

M3 - Article

C2 - 31036624

SN - 0003-4967

VL - 78

SP - 1055

EP - 1061

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 8

ER -

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

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