Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39
ObjectivesWe 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.Meth...
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| Veröffentlicht in: | Annals of the rheumatic diseases 2019-08, Vol.78 (8), p.1055-1061 |
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| container_title | Annals of the rheumatic diseases |
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| creator | Spiliopoulou, Athina Colombo, Marco Plant, Darren Nair, Nisha Cui, Jing Coenen, Marieke JH Ikari, Katsunori Yamanaka, Hisashi Saevarsdottir, Saedis Padyukov, Leonid Bridges Jr, S Louis Kimberly, Robert P Okada, Yukinori van Riel, Piet L CM Wolbink, Gertjan van der Horst-Bruinsma, Irene E de Vries, Niek Tak, Paul P Ohmura, Koichiro Canhão, Helena Guchelaar, Henk-Jan Huizinga, Tom WJ Criswell, Lindsey A Raychaudhuri, Soumya Weinblatt, Michael E Wilson, Anthony G Mariette, Xavier Isaacs, John D Morgan, Ann W Pitzalis, Costantino Barton, Anne McKeigue, Paul |
| description | ObjectivesWe 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.MethodsWe 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.ResultsWe 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.ConclusionsThe 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. |
| doi_str_mv | 10.1136/annrheumdis-2018-214877 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_D8T</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_480148</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2257160425</sourcerecordid><originalsourceid>FETCH-LOGICAL-b598t-81a6bd4b0ca4f8fa5407c612b82c74f78cc4b6624abcf3f12c34b95aafb188ff3</originalsourceid><addsrcrecordid>eNqVUl1vFCEUJUZj1-pfUBKfR_kaYF5Mmq21TRp9qc8EGHBZd2ELTBv_vayzru2Lxifu5Z5zuOdyAXiD0TuMKX-vY8wrN23HUDqCsOwIZlKIJ2CBGW8Z4ugpWCCEaMcGLk7Ai1LWLUUSy-fghGJEOSdsAXZnpSQbdA0pwuRhdmWXYnGwJnjz-QKGuAom1JRLC-GvN3VNYYQ611UONRR4H-oK3k461lCbzl3jZh0q3DRd6FOGy3OGoI5jC-jwEjzzelPcq8N5Cr5efLxZXnbXXz5dLc-uO9MPsnYSa25GZpDVzEuve4aE5ZgYSaxgXkhrmdlb0MZ66jGxlJmh19obLKX39BR0s265d7vJqF0OW51_qKSDOlx9b5FTTKI2u4b_MONbZetG62JzsXlEe1yJYaW-pTvFOR-o2Au8PQjkdDu5UtU6TTk2j6qNm2EiyED-hiKkF5gjRvqGEjPK5lRKdv7YB0ZqvwDqwQKo_QKoeQEa8_VDG0fe7x9vADIDzHb9H6r0D-nY8L9YPwHyMtMO</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2257160425</pqid></control><display><type>article</type><title>Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39</title><source>SWEPUB Freely available online</source><creator>Spiliopoulou, Athina ; Colombo, Marco ; Plant, Darren ; Nair, Nisha ; Cui, Jing ; Coenen, Marieke JH ; Ikari, Katsunori ; Yamanaka, Hisashi ; Saevarsdottir, Saedis ; Padyukov, Leonid ; Bridges Jr, S Louis ; Kimberly, Robert P ; Okada, Yukinori ; van Riel, Piet L CM ; Wolbink, Gertjan ; van der Horst-Bruinsma, Irene E ; de Vries, Niek ; Tak, Paul P ; Ohmura, Koichiro ; Canhão, Helena ; Guchelaar, Henk-Jan ; Huizinga, Tom WJ ; Criswell, Lindsey A ; Raychaudhuri, Soumya ; Weinblatt, Michael E ; Wilson, Anthony G ; Mariette, Xavier ; Isaacs, John D ; Morgan, Ann W ; Pitzalis, Costantino ; Barton, Anne ; McKeigue, Paul</creator><creatorcontrib>Spiliopoulou, Athina ; Colombo, Marco ; Plant, Darren ; Nair, Nisha ; Cui, Jing ; Coenen, Marieke JH ; Ikari, Katsunori ; Yamanaka, Hisashi ; Saevarsdottir, Saedis ; Padyukov, Leonid ; Bridges Jr, S Louis ; Kimberly, Robert P ; Okada, Yukinori ; van Riel, Piet L CM ; Wolbink, Gertjan ; van der Horst-Bruinsma, Irene E ; de Vries, Niek ; Tak, Paul P ; Ohmura, Koichiro ; Canhão, Helena ; Guchelaar, Henk-Jan ; Huizinga, Tom WJ ; Criswell, Lindsey A ; Raychaudhuri, Soumya ; Weinblatt, Michael E ; Wilson, Anthony G ; Mariette, Xavier ; Isaacs, John D ; Morgan, Ann W ; Pitzalis, Costantino ; Barton, Anne ; McKeigue, Paul</creatorcontrib><description>ObjectivesWe 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.MethodsWe 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.ResultsWe 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.ConclusionsThe 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.</description><identifier>ISSN: 0003-4967</identifier><identifier>EISSN: 1468-2060</identifier><identifier>DOI: 10.1136/annrheumdis-2018-214877</identifier><identifier>PMID: 31036624</identifier><language>eng</language><publisher>England: BMJ Publishing Group Ltd and European League Against Rheumatism</publisher><subject>Adult ; Aged ; anti-tnf ; Antigens, CD - genetics ; Antirheumatic Agents - therapeutic use ; Apyrase - genetics ; Arthritis, Rheumatoid - diagnosis ; Arthritis, Rheumatoid - drug therapy ; Arthritis, Rheumatoid - genetics ; Biological Products - therapeutic use ; Biomarkers ; CD4 antigen ; CD40 antigen ; CD40 Antigens - genetics ; Cell culture ; Cohort Studies ; Crowdsourcing ; Disease ; DNA methylation ; Drug therapy ; Erythrocyte sedimentation rate ; Female ; Gene Expression Regulation ; Gene loci ; Genetics ; Genome-Wide Association Study ; Genomes ; Genomics ; Health risk assessment ; Health sciences ; Humans ; Immunoregulation ; Informatics ; Lymphocytes T ; Male ; Methotrexate ; Middle Aged ; Molecular Targeted Therapy - methods ; Multivariate Analysis ; pharmacogenetics ; Phenotypic variations ; Predictive Value of Tests ; Prognosis ; Quantitative trait loci ; Quantitative Trait Loci - genetics ; Regression Analysis ; Rheumatoid Arthritis ; Statistical analysis ; Studies ; TNF inhibitors ; Transcription ; Treatment Outcome ; Tumor necrosis factor ; Tumor Necrosis Factor Inhibitors - therapeutic use ; Tumor necrosis factor-TNF</subject><ispartof>Annals of the rheumatic diseases, 2019-08, Vol.78 (8), p.1055-1061</ispartof><rights>Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.</rights><rights>2019 Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b598t-81a6bd4b0ca4f8fa5407c612b82c74f78cc4b6624abcf3f12c34b95aafb188ff3</citedby><cites>FETCH-LOGICAL-b598t-81a6bd4b0ca4f8fa5407c612b82c74f78cc4b6624abcf3f12c34b95aafb188ff3</cites><orcidid>0000-0003-1326-5051 ; 0000-0002-5929-6585</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,550,776,881</link.rule.ids><linktorsrc>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:141783424$$EView_record_in_Swedish_Publication_Index_(SWEPUB)$$FView_record_in_$$GSwedish_Publication_Index_(SWEPUB)$$Hfree_for_read</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31036624$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:141783424$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Spiliopoulou, Athina</creatorcontrib><creatorcontrib>Colombo, Marco</creatorcontrib><creatorcontrib>Plant, Darren</creatorcontrib><creatorcontrib>Nair, Nisha</creatorcontrib><creatorcontrib>Cui, Jing</creatorcontrib><creatorcontrib>Coenen, Marieke JH</creatorcontrib><creatorcontrib>Ikari, Katsunori</creatorcontrib><creatorcontrib>Yamanaka, Hisashi</creatorcontrib><creatorcontrib>Saevarsdottir, Saedis</creatorcontrib><creatorcontrib>Padyukov, Leonid</creatorcontrib><creatorcontrib>Bridges Jr, S Louis</creatorcontrib><creatorcontrib>Kimberly, Robert P</creatorcontrib><creatorcontrib>Okada, Yukinori</creatorcontrib><creatorcontrib>van Riel, Piet L CM</creatorcontrib><creatorcontrib>Wolbink, Gertjan</creatorcontrib><creatorcontrib>van der Horst-Bruinsma, Irene E</creatorcontrib><creatorcontrib>de Vries, Niek</creatorcontrib><creatorcontrib>Tak, Paul P</creatorcontrib><creatorcontrib>Ohmura, Koichiro</creatorcontrib><creatorcontrib>Canhão, Helena</creatorcontrib><creatorcontrib>Guchelaar, Henk-Jan</creatorcontrib><creatorcontrib>Huizinga, Tom WJ</creatorcontrib><creatorcontrib>Criswell, Lindsey A</creatorcontrib><creatorcontrib>Raychaudhuri, Soumya</creatorcontrib><creatorcontrib>Weinblatt, Michael E</creatorcontrib><creatorcontrib>Wilson, Anthony G</creatorcontrib><creatorcontrib>Mariette, Xavier</creatorcontrib><creatorcontrib>Isaacs, John D</creatorcontrib><creatorcontrib>Morgan, Ann W</creatorcontrib><creatorcontrib>Pitzalis, Costantino</creatorcontrib><creatorcontrib>Barton, Anne</creatorcontrib><creatorcontrib>McKeigue, Paul</creatorcontrib><title>Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39</title><title>Annals of the rheumatic diseases</title><addtitle>Ann Rheum Dis</addtitle><addtitle>Ann Rheum Dis</addtitle><description>ObjectivesWe 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.MethodsWe 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.ResultsWe 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.ConclusionsThe 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.</description><subject>Adult</subject><subject>Aged</subject><subject>anti-tnf</subject><subject>Antigens, CD - genetics</subject><subject>Antirheumatic Agents - therapeutic use</subject><subject>Apyrase - genetics</subject><subject>Arthritis, Rheumatoid - diagnosis</subject><subject>Arthritis, Rheumatoid - drug therapy</subject><subject>Arthritis, Rheumatoid - genetics</subject><subject>Biological Products - therapeutic use</subject><subject>Biomarkers</subject><subject>CD4 antigen</subject><subject>CD40 antigen</subject><subject>CD40 Antigens - genetics</subject><subject>Cell culture</subject><subject>Cohort Studies</subject><subject>Crowdsourcing</subject><subject>Disease</subject><subject>DNA methylation</subject><subject>Drug therapy</subject><subject>Erythrocyte sedimentation rate</subject><subject>Female</subject><subject>Gene Expression Regulation</subject><subject>Gene loci</subject><subject>Genetics</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Health risk assessment</subject><subject>Health sciences</subject><subject>Humans</subject><subject>Immunoregulation</subject><subject>Informatics</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Methotrexate</subject><subject>Middle Aged</subject><subject>Molecular Targeted Therapy - methods</subject><subject>Multivariate Analysis</subject><subject>pharmacogenetics</subject><subject>Phenotypic variations</subject><subject>Predictive Value of Tests</subject><subject>Prognosis</subject><subject>Quantitative trait loci</subject><subject>Quantitative Trait Loci - genetics</subject><subject>Regression Analysis</subject><subject>Rheumatoid Arthritis</subject><subject>Statistical analysis</subject><subject>Studies</subject><subject>TNF inhibitors</subject><subject>Transcription</subject><subject>Treatment Outcome</subject><subject>Tumor necrosis factor</subject><subject>Tumor Necrosis Factor Inhibitors - therapeutic use</subject><subject>Tumor necrosis 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of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39</title><author>Spiliopoulou, Athina ; Colombo, Marco ; Plant, Darren ; Nair, Nisha ; Cui, Jing ; Coenen, Marieke JH ; Ikari, Katsunori ; Yamanaka, Hisashi ; Saevarsdottir, Saedis ; Padyukov, Leonid ; Bridges Jr, S Louis ; Kimberly, Robert P ; Okada, Yukinori ; van Riel, Piet L CM ; Wolbink, Gertjan ; van der Horst-Bruinsma, Irene E ; de Vries, Niek ; Tak, Paul P ; Ohmura, Koichiro ; Canhão, Helena ; Guchelaar, Henk-Jan ; Huizinga, Tom WJ ; Criswell, Lindsey A ; Raychaudhuri, Soumya ; Weinblatt, Michael E ; Wilson, Anthony G ; Mariette, Xavier ; Isaacs, John D ; Morgan, Ann W ; Pitzalis, Costantino ; Barton, Anne ; McKeigue, Paul</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b598t-81a6bd4b0ca4f8fa5407c612b82c74f78cc4b6624abcf3f12c34b95aafb188ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adult</topic><topic>Aged</topic><topic>anti-tnf</topic><topic>Antigens, CD - genetics</topic><topic>Antirheumatic Agents - therapeutic use</topic><topic>Apyrase - genetics</topic><topic>Arthritis, Rheumatoid - diagnosis</topic><topic>Arthritis, Rheumatoid - drug therapy</topic><topic>Arthritis, Rheumatoid - genetics</topic><topic>Biological Products - therapeutic use</topic><topic>Biomarkers</topic><topic>CD4 antigen</topic><topic>CD40 antigen</topic><topic>CD40 Antigens - genetics</topic><topic>Cell culture</topic><topic>Cohort Studies</topic><topic>Crowdsourcing</topic><topic>Disease</topic><topic>DNA methylation</topic><topic>Drug therapy</topic><topic>Erythrocyte sedimentation 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(Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Annals of the rheumatic diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Spiliopoulou, Athina</au><au>Colombo, Marco</au><au>Plant, Darren</au><au>Nair, Nisha</au><au>Cui, Jing</au><au>Coenen, Marieke JH</au><au>Ikari, Katsunori</au><au>Yamanaka, Hisashi</au><au>Saevarsdottir, Saedis</au><au>Padyukov, Leonid</au><au>Bridges Jr, S Louis</au><au>Kimberly, Robert P</au><au>Okada, Yukinori</au><au>van Riel, Piet L CM</au><au>Wolbink, Gertjan</au><au>van der Horst-Bruinsma, Irene E</au><au>de Vries, Niek</au><au>Tak, Paul P</au><au>Ohmura, Koichiro</au><au>Canhão, Helena</au><au>Guchelaar, Henk-Jan</au><au>Huizinga, Tom WJ</au><au>Criswell, Lindsey A</au><au>Raychaudhuri, Soumya</au><au>Weinblatt, Michael E</au><au>Wilson, Anthony G</au><au>Mariette, Xavier</au><au>Isaacs, John D</au><au>Morgan, Ann W</au><au>Pitzalis, Costantino</au><au>Barton, Anne</au><au>McKeigue, Paul</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39</atitle><jtitle>Annals of the rheumatic diseases</jtitle><stitle>Ann Rheum Dis</stitle><addtitle>Ann Rheum Dis</addtitle><date>2019-08-01</date><risdate>2019</risdate><volume>78</volume><issue>8</issue><spage>1055</spage><epage>1061</epage><pages>1055-1061</pages><issn>0003-4967</issn><eissn>1468-2060</eissn><abstract>ObjectivesWe 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.MethodsWe 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.ResultsWe 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.ConclusionsThe 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.</abstract><cop>England</cop><pub>BMJ Publishing Group Ltd and European League Against Rheumatism</pub><pmid>31036624</pmid><doi>10.1136/annrheumdis-2018-214877</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0003-1326-5051</orcidid><orcidid>https://orcid.org/0000-0002-5929-6585</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext_linktorsrc |
| identifier | ISSN: 0003-4967 |
| ispartof | Annals of the rheumatic diseases, 2019-08, Vol.78 (8), p.1055-1061 |
| issn | 0003-4967 1468-2060 |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_480148 |
| source | SWEPUB Freely available online |
| subjects | Adult Aged anti-tnf Antigens, CD - genetics Antirheumatic Agents - therapeutic use Apyrase - genetics Arthritis, Rheumatoid - diagnosis Arthritis, Rheumatoid - drug therapy Arthritis, Rheumatoid - genetics Biological Products - therapeutic use Biomarkers CD4 antigen CD40 antigen CD40 Antigens - genetics Cell culture Cohort Studies Crowdsourcing Disease DNA methylation Drug therapy Erythrocyte sedimentation rate Female Gene Expression Regulation Gene loci Genetics Genome-Wide Association Study Genomes Genomics Health risk assessment Health sciences Humans Immunoregulation Informatics Lymphocytes T Male Methotrexate Middle Aged Molecular Targeted Therapy - methods Multivariate Analysis pharmacogenetics Phenotypic variations Predictive Value of Tests Prognosis Quantitative trait loci Quantitative Trait Loci - genetics Regression Analysis Rheumatoid Arthritis Statistical analysis Studies TNF inhibitors Transcription Treatment Outcome Tumor necrosis factor Tumor Necrosis Factor Inhibitors - therapeutic use Tumor necrosis factor-TNF |
| title | Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39 |
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