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Genome Biol. 2018 Oct 19;19(1):168. doi: 10.1186/s13059-018-1560-8.

Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial.

Davenport EE1,2,3,4, Amariuta T1,2,3,4,5, Gutierrez-Arcelus M1,2,3,4, Slowikowski K1,2,3,4,5, Westra HJ1,2,3,4, Luo Y1,2,3,4, Shen C6, Rao DA7, Zhang Y8, Pearson S9, von Schack D8, Beebe JS8, Bing N8, John S10, Vincent MS8, Zhang B8, Raychaudhuri S11,12,13,14,15,16,17.

Author information

1
Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, 02115, USA.
2
Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
3
Partners Center for Personalized Genetic Medicine, Boston, MA, 02115, USA.
4
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
5
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA.
6
Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
7
Division of Rheumatology, Allergy, Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
8
Pfizer Inc., Cambridge, MA, 02139, USA.
9
Pfizer New Haven Clinical Research Unit, New Haven, CT, 06511, USA.
10
Biogen, Cambridge, MA, 02142, USA.
11
Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, 02115, USA. soumya@broadinstitute.org.
12
Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. soumya@broadinstitute.org.
13
Partners Center for Personalized Genetic Medicine, Boston, MA, 02115, USA. soumya@broadinstitute.org.
14
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. soumya@broadinstitute.org.
15
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA. soumya@broadinstitute.org.
16
Faculty of Medical and Human Sciences, University of Manchester, M13 9PL, Manchester, UK. soumya@broadinstitute.org.
17
Harvard New Research Building, 77 Avenue Louis Pasteur, Suite 250D, Boston, MA, 02446, USA. soumya@broadinstitute.org.

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.

KEYWORDS:

Clinical trials; Cytokines; Interactions; eQTL

PMID:
30340504
PMCID:
PMC6195724
DOI:
10.1186/s13059-018-1560-8
[Indexed for MEDLINE]
Free PMC Article

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