Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial
Abstract Background Cytokines are critical to human disease and are attractive therapeutic targets given their widespread influence on gene regulation and transcription. Defining the downstream regulatory mechanisms influenced by cytokines is central to defining drug and disease mechanisms. One prom...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-10-01
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| Series: | Genome Biology |
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| Online Access: | http://link.springer.com/article/10.1186/s13059-018-1560-8 |
| _version_ | 1819277775498903552 |
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| author | Emma E. Davenport Tiffany Amariuta Maria Gutierrez-Arcelus Kamil Slowikowski Harm-Jan Westra Yang Luo Ciyue Shen Deepak A. Rao Ying Zhang Stephen Pearson David von Schack Jean S. Beebe Nan Bing Sally John Michael S. Vincent Baohong Zhang Soumya Raychaudhuri |
| author_facet | Emma E. Davenport Tiffany Amariuta Maria Gutierrez-Arcelus Kamil Slowikowski Harm-Jan Westra Yang Luo Ciyue Shen Deepak A. Rao Ying Zhang Stephen Pearson David von Schack Jean S. Beebe Nan Bing Sally John Michael S. Vincent Baohong Zhang Soumya Raychaudhuri |
| author_sort | Emma E. Davenport |
| collection | DOAJ |
| description | Abstract Background Cytokines are critical to human disease and are attractive therapeutic targets given their widespread influence on gene regulation and transcription. Defining the downstream regulatory mechanisms influenced by cytokines is central to defining drug and disease mechanisms. One promising strategy is to use interactions between expression quantitative trait loci (eQTLs) and cytokine levels to define target genes and mechanisms. Results In a clinical trial for anti-IL-6 in patients with systemic lupus erythematosus, we measure interferon (IFN) status, anti-IL-6 drug exposure, and whole blood genome-wide gene expression at three time points. We show that repeat transcriptomic measurements increases the number of cis eQTLs identified compared to using a single time point. We observe a statistically significant enrichment of in vivo eQTL interactions with IFN status and anti-IL-6 drug exposure and find many novel interactions that have not been previously described. Finally, we find transcription factor binding motifs interrupted by eQTL interaction SNPs, which point to key regulatory mediators of these environmental stimuli and therefore potential therapeutic targets for autoimmune diseases. In particular, genes with IFN interactions are enriched for ISRE binding site motifs, while those with anti-IL-6 interactions are enriched for IRF4 motifs. Conclusions This study highlights the potential to exploit clinical trial data to discover in vivo eQTL interactions with therapeutically relevant environmental variables. |
| first_indexed | 2024-12-24T00:01:28Z |
| format | Article |
| id | doaj.art-8075e72d26c1477fb0d4a12d32759788 |
| institution | Directory Open Access Journal |
| issn | 1474-760X |
| language | English |
| last_indexed | 2024-12-24T00:01:28Z |
| publishDate | 2018-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj.art-8075e72d26c1477fb0d4a12d327597882022-12-21T17:25:07ZengBMCGenome Biology1474-760X2018-10-0119111510.1186/s13059-018-1560-8Discovering in vivo cytokine-eQTL interactions from a lupus clinical trialEmma E. Davenport0Tiffany Amariuta1Maria Gutierrez-Arcelus2Kamil Slowikowski3Harm-Jan Westra4Yang Luo5Ciyue Shen6Deepak A. Rao7Ying Zhang8Stephen Pearson9David von Schack10Jean S. Beebe11Nan Bing12Sally John13Michael S. Vincent14Baohong Zhang15Soumya Raychaudhuri16Center for Data Sciences, Brigham and Women’s HospitalCenter for Data Sciences, Brigham and Women’s HospitalCenter for Data Sciences, Brigham and Women’s HospitalCenter for Data Sciences, Brigham and Women’s HospitalCenter for Data Sciences, Brigham and Women’s HospitalCenter for Data Sciences, Brigham and Women’s HospitalDepartment of Cell Biology, Harvard Medical SchoolDivision of Rheumatology, Allergy, Immunology, Brigham and Women’s Hospital, Harvard Medical SchoolPfizer Inc.Pfizer New Haven Clinical Research UnitPfizer Inc.Pfizer Inc.Pfizer Inc.BiogenPfizer Inc.Pfizer Inc.Center for Data Sciences, Brigham and Women’s HospitalAbstract Background Cytokines are critical to human disease and are attractive therapeutic targets given their widespread influence on gene regulation and transcription. Defining the downstream regulatory mechanisms influenced by cytokines is central to defining drug and disease mechanisms. One promising strategy is to use interactions between expression quantitative trait loci (eQTLs) and cytokine levels to define target genes and mechanisms. Results In a clinical trial for anti-IL-6 in patients with systemic lupus erythematosus, we measure interferon (IFN) status, anti-IL-6 drug exposure, and whole blood genome-wide gene expression at three time points. We show that repeat transcriptomic measurements increases the number of cis eQTLs identified compared to using a single time point. We observe a statistically significant enrichment of in vivo eQTL interactions with IFN status and anti-IL-6 drug exposure and find many novel interactions that have not been previously described. Finally, we find transcription factor binding motifs interrupted by eQTL interaction SNPs, which point to key regulatory mediators of these environmental stimuli and therefore potential therapeutic targets for autoimmune diseases. In particular, genes with IFN interactions are enriched for ISRE binding site motifs, while those with anti-IL-6 interactions are enriched for IRF4 motifs. Conclusions This study highlights the potential to exploit clinical trial data to discover in vivo eQTL interactions with therapeutically relevant environmental variables.http://link.springer.com/article/10.1186/s13059-018-1560-8eQTLInteractionsClinical trialsCytokines |
| spellingShingle | Emma E. Davenport Tiffany Amariuta Maria Gutierrez-Arcelus Kamil Slowikowski Harm-Jan Westra Yang Luo Ciyue Shen Deepak A. Rao Ying Zhang Stephen Pearson David von Schack Jean S. Beebe Nan Bing Sally John Michael S. Vincent Baohong Zhang Soumya Raychaudhuri Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial Genome Biology eQTL Interactions Clinical trials Cytokines |
| title | Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial |
| title_full | Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial |
| title_fullStr | Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial |
| title_full_unstemmed | Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial |
| title_short | Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial |
| title_sort | discovering in vivo cytokine eqtl interactions from a lupus clinical trial |
| topic | eQTL Interactions Clinical trials Cytokines |
| url | http://link.springer.com/article/10.1186/s13059-018-1560-8 |
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