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Immune disease variants modulate gene expression in regulatory CD4+ T cells and inform drug targets

By Lara Bossini-Castillo, Dafni A. Glinos, Natalia Kunowska, Gosia Golda, Abigail Lamikanra, Michaela Spitzer, Blagoje Soskic, Eddie Cano-Gamez, Deborah J. Smyth, Claire Cattermole, Kaur Alasoo, Alice Mann, Kousik Kundu, Nicole Soranzo, Ian Dunham, David Roberts, Soumya Raychaudhuri

Posted 31 May 2019
bioRxiv DOI: 10.1101/654632

Identifying cellular functions dysregulated by disease associated variants could implicate novel pathways for drug targeting or modulation in cell therapies. Variants associated with immune diseases point towards the role of CD4+ regulatory T cells (Tregs), cell type critical for immune homeostasis. To translate the effects of immune disease alleles on Treg function we mapped genetic regulation (QTL) of gene expression and chromatin activity in Tregs. We identified 123 loci where Treg QTLs colocalized with immune disease variants. These colocalizations indicated that dysregulation of key Treg pathways, including cell activation via CD28 and IL-2 signalling mediated by STAT5A contribute to the shared pathobiology of immune diseases. Finally, using disease GWAS signals colocalizing with Treg QTLs, we identified 34 known drug targets and 270 targets with drug tractability evidence. Our study is the first in-depth characterization of immune disease variant effects on Treg gene expression modulation and dysregulation of Treg function.

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