Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell dysregulation and type 1 interferon (IFN) activity. Variants in the major histocompatibility complex (MHC) region confer the greatest genetic risk for SLE; however, the underlying causes of association remain elusive. One mechanism by which causal variants may drive genetic associations at the MHC is through regulating gene expression in a context-specific manner. This project investigates the effect of (i) SLE-associated MHC haplotypes, and (ii) IFN-α stimulation on gene regulation in ex vivo B cells, in order to further our understanding of how these factors contribute to disease risk. Expression quantitative trait loci (eQTLs) were investigated for variants tagging six SLE-risk or -protective haplotypes: DRB1*03:01 (rs2187668), DRB1*15:01 (rs3135391), DPB1 (rs3117213, rs2071351, rs2071349), and MSH5 (rs409558). eQTL analyses were conducted using publicly-available data sets. Additionally, gene expression data were generated from resting and IFN-α-stimulated ex vivo B cells. Several cis-eQTLs were identified and replicated in the publicly-available data sets. A novel trans-eQTL was identified for DRB1*03:01 haplotypes in the exon array data set, in both resting and IFN-α-stimulated cells, involving down-regulation of BTN3A2 (P < 2.63 × 10-6). These results suggest a regulatory role for disease-associated MHC haplotypes, and implicate BTN3A2 as a novel candidate gene on the DRB1*03:01 haplotype. The global effect of IFN-α stimulation on the B cell transcriptome was also explored. Several SLE susceptibility genes outside canonical type 1 IFN signalling pathways were differentially expressed in response to IFN-α. The direction of effect of IFN-α on the expression of SLE candidate genes paralleled the known functional consequences of SLE-associated polymorphisms in those genes. This suggests a previously unrecognised role for SLE candidate genes following activation of the type 1 IFN pathway, and sheds light into the role of IFN-α in the aetiopathogenesis of SLE.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:713105 |
| Date | January 2017 |
| Creators | Salgado Teixeira Duarte, Carolina |
| Contributors | Fernando, Maria Michelle Agatha ; Vyse, Timothy James |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/the-role-of-lupus-susceptibility-mhc-haplotypes-and-interferonalpha-in-gene-regulation(7430456f-6cca-47e0-b9f4-a89a22e1991f).html |
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