1. OP0113 FUNCTIONAL GENOMICS IN PRIMARY T CELLS AND MONOCYTES IDENTIFIES MECHANISMS BY WHICH GENETIC SUSCEPTIBILITY LOCI INFLUENCE SYSTEMIC SCLEROSIS RISK
- Author
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D. Gonzalez Serna, C. Shi, M. Kerick, J. Hankinson, J. Ding, A. McGovern, M. Tutino, N. Ortego, J. L. Callejas-Rubio, J. Martin Ibanez, and G. Orozco
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Rheumatology ,Immunology ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
BackgroundSystemic sclerosis (SSc) is a complex autoimmune disease with a strong genetic component. However, the underlying mechanism by which genetics increase disease risk is still unknown. The most recent GWAS studies have identified 27 independent signals associated to SSc [1]. However, the majority of these signals affect regulatory elements that can regulate genes often located hundreds of kilobases away.The challenge in the post-GWAS era is to use functional genomics to translate genetic findings into patients’ benefit, particularly in disease-relevant cell types.ObjectivesIn this study we use chromatin conformation and gene expression analysis in patient derived primary cells and healthy individuals to assess potential mechanisms by which GWAS variants increase disease risk. We identify the potentially affected genes in a cell type specific manner and potential drug targets already in use or with potential for re-purposing.MethodsPromoter capture Hi-C (pCHi-C) and RNA sequencing experiments were performed in a total of 15 CD4+ T cells and CD14+ monocytes samples each isolated from peripheral blood from SSc patients and healthy controls. We linked SSc-associated variants with their target genes and performed differential expression and differential interaction analyses between both cell types. Potential drug targets were identified using a protein-protein interaction model and queried against the OpenTargets database.ResultsWe linked SSc-associated loci to 39 new potential target genes, confirming 7 previously assigned genes. We highlight novel causal genes, such as CXCR5 as the most probable candidate gene for the DDX6 locus (Figure 1). We confirm some previously linked SSc genes such as IRF8, STAT4, or CD247 which interestingly showed cell type specific interactions. We also identified 15 potential drug targets already in use in other similar immune-mediated diseases that could be repurposed for SSc treatment. Furthermore, we observed that interactions are directly related with the expression of important genes implicated in cell type specific pathways.Figure 1.Promoter Capture Hi-C interactions linking the DDX6 GWAS loci with the promoter of CXCR5 in CD4+ T cells and CD14+ monocytes. CD4+ T cells show significantly stronger interactions as well as CXCR5 gene expression.ConclusionOur study reveals potential causal genes for SSc-associated loci, some of them acting in a cell type specific manner, suggesting novel drug targets and biological mechanisms that may mediate SSc pathogenesis.References[1]López-Isac E, Acosta-Herrera M, Kerick M, et al (2019) GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways. Nat Commun 10:. https://doi.org/10.1038/s41467-019-12760-yAcknowledgementsThis work was supported by the Spanish Ministry of Science and Innovation (grants RTI2018101332-B-100 and SAF2015-66761-P), the Cooperative Research Thematic Network (RETICS) programme (RD16/0012/0013) (RIER) from Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Economy, Industry and Competitiveness), the Wellcome Trust (award references 207491/Z/17/Z and 215207/Z/19/Z), Versus Arthritis (award reference 21754), and the NIHR Manchester Biomedical Research Centre. DGS was supported by the Spanish Ministry of Economy and Competitiveness through the FPI programme (SAF2015-66761-P).Disclosure of InterestsNone declared
- Published
- 2022
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