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Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial
Emma E Davenport1,2,3,4, Tiffany Amariuta1,2,3,4,5, Maria Gutierrez-Arcelus1,2,3,4
1Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, 02115, USA.
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.
Insights
This study reveals how analyzing gene expression data from clinical trials can uncover new ways cytokines like interferon and anti-IL-6 influence autoimmune diseases, identifying potential therapeutic targets.
Area of Science:
- Immunology
- Genetics
- Pharmacology
Background:
- Cytokines play a crucial role in human diseases and are key therapeutic targets due to their broad impact on gene regulation.
- Understanding cytokine-driven regulatory mechanisms is essential for elucidating drug and disease pathways.
- Expression quantitative trait loci (eQTLs) interacting with cytokine levels offer a promising strategy to identify target genes and mechanisms.
Purpose of the Study:
- To investigate in vivo eQTL interactions with environmental variables using clinical trial data.
- To identify novel regulatory mechanisms and potential therapeutic targets in autoimmune diseases.
Main Methods:
- Collected whole blood genome-wide gene expression data at three time points during a clinical trial for anti-interleukin-6 (anti-IL-6) in systemic lupus erythematosus patients.
- Measured interferon (IFN) status and anti-IL-6 drug exposure.
- Analyzed cis eQTLs and their interactions with IFN status and anti-IL-6 drug exposure.
Main Results:
- Repeated transcriptomic measurements identified more cis eQTLs than single-time point measurements.
- Observed statistically significant enrichment of in vivo eQTL interactions with IFN status and anti-IL-6 drug exposure, revealing novel interactions.
- Identified transcription factor binding motifs (ISRE for IFN, IRF4 for anti-IL-6) disrupted by eQTL interaction SNPs, indicating key regulatory mediators.
Conclusions:
- Clinical trial data can be effectively utilized to discover in vivo eQTL interactions with relevant environmental factors.
- This approach can identify novel therapeutic targets for autoimmune diseases by pinpointing key regulatory mediators of environmental stimuli.
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