Immune disease variants modulate gene expression in regulatory CD4+ T cells

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

doi:10.1016/j.xgen.2022.100117

Immune disease variants modulate gene expression in regulatory CD4⁺ T cells

Cell Genom. 2022 Apr 13;2(4):None. doi: 10.1016/j.xgen.2022.100117.

Authors

Lara Bossini-Castillo¹, Dafni A Glinos^{1

2}, Natalia Kunowska¹, Gosia Golda¹, Abigail A Lamikanra^{3

4}, Michaela Spitzer^{5

6}, Blagoje Soskic^{1

6}, Eddie Cano-Gamez^{1

6}, Deborah J Smyth^{1

6}, Claire Cattermole¹, Kaur Alasoo^{1

7}, Alice Mann¹, Kousik Kundu¹, Anna Lorenc¹, Nicole Soranzo¹, Ian Dunham^{5

6}, David J Roberts^{3

4}, Gosia Trynka^{1

6}

Affiliations

¹ Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
² New York Genome Center, New York, NY, USA.
³ NHS Blood and Transplant, Oxford, UK.
⁴ BRC Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁵ European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK.
⁶ Open Targets, Wellcome Genome Campus, Cambridge, UK.
⁷ Institute of Computer Science, University of Tartu, Tartu, Estonia.

Abstract

Identifying cellular functions dysregulated by disease-associated variants could implicate novel pathways for drug targeting or modulation in cell therapies. However, follow-up studies can be challenging if disease-relevant cell types are difficult to sample. Variants associated with immune diseases point toward the role of CD4⁺ regulatory T cells (Treg cells). We mapped genetic regulation (quantitative trait loci [QTL]) of gene expression and chromatin activity in Treg cells, and we identified 133 colocalizing loci with immune disease variants. Colocalizations of immune disease genome-wide association study (GWAS) variants with expression QTLs (eQTLs) controlling the expression of CD28 and STAT5A, involved in Treg cell activation and interleukin-2 (IL-2) signaling, support the contribution of Treg cells to the pathobiology of immune diseases. Finally, we identified seven known drug targets suitable for drug repurposing and suggested 63 targets with drug tractability evidence among the GWAS signals that colocalized with Treg cell QTLs. Our study is the first in-depth characterization of immune disease variant effects on Treg cell gene expression modulation and dysregulation of Treg cell function.

Keywords: GWAS; autoimmunity; epigenomics; expression quantitative trait loci; immune disease; immune system; quantitative trait loci; regulatory T cell; transcriptomics.

Abstract

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