Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Systemic lupus erythematosus (SLE) is a complex genetic autoimmune disease characterized by autoantibody production and up-regulation of type 1 interferons (IFNs). The strongest genetic association in Europeans is tagged by the HLA-DRB1*03:01 extended haplotype, located in the MHC region on chromosome 6. Due to tight linkage disequilibrium and high polymorphism, the molecular mechanisms underlying the DRB1*03:01 association remain elusive. Coding and non-coding variants arising from this haplotype may play a role in disease susceptibility through regulating gene expression in a context-specific manner.
We therefore sought to investigate the effect of the SLE susceptibility factors (i) IFN-α and (ii) the DRB1*03:01 haplotype on gene expression in ex vivo B cells.
Methods: Fifty healthy European women harbouring DRB1*03:01 homozygous (n=17), heterozygous (n=3) and non-DRB1*03:01 (n=30) haplotypes were included in the study. RNA was extracted from negatively-selected ex vivoB cells at rest (n=49) and after stimulation with IFN-α (n=33). Genome-wide gene expression levels were quantified using the Affymetrix Human Exon 1.0 ST array and TaqMan qPCR. Differential expression was calculated using an ANOVA in Partek Genomics Suite and R (FDR<1%).
Results: Thirty-three per cent (5,163 / 15,468) of genes genome-wide are differentially expressed between resting and IFN-α-treated cells. Forty per cent of SLE (p=4×10-2) and 53% (p=6×10-6) of RA susceptibility genes from genome-wide association studies are significantly enriched in this data set, compared to IBD (30%, p=0.07).
As expected, these include members of the type 1 IFN pathway, such as the SLE risk genes IRF7 (fold change, FC=7.2) and STAT4 (FC=6.8). Interestingly, a number of SLE genes outside canonical type 1 IFN pathways are significantly down-regulated in response to IFN-α, including FCGR2B (FC=-2.7), ETS1 (FC=-1.7) and NCF2 (FC=-2.3). In addition, IFN-α decreases the expression of genes implicated in familial SLE, such as the B cell survival gene, PRKCD (FC=-1.2).
Furthermore, we find that the MHC class II gene, HLA-DPB1, is significantly up-regulated in DRB1*03:01 haplotypes compared to non-DRB1*03:01haplotypes at a similar level in resting cells and IFN-α-stimulated cells (FC=1.2).
Conclusion: Stimulation of B cells with IFN-α significantly alters expression of genes associated with idiopathic and familial SLE not previously reported to be involved in the type 1 IFN response. Down-regulation of a number of these genes by IFN-α parallels previously reported loss-of-function polymorphisms associated with SLE susceptibility. We also report a cis-eQTL (expression quantitative trait locus) between the DRB1*03:01 haplotype and HLA-DPB1, implicating a role for this haplotype in gene regulation. These data shed light into the role of IFN-α in the aetiopathogenesis of SLE and implicate HLA-DPB1 as an additional candidate gene underlying the DRB1*03:01 association with autoimmunity.
To cite this abstract in AMA style:Duarte C, Boteva L, Vyse T, Fernando M. Differential Expression of SLE Susceptibility Genes By Interferon-Alpha and the HLA-DRB1*03:01 Haplotype in Ex Vivo B Cells [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/differential-expression-of-sle-susceptibility-genes-by-interferon-alpha-and-the-hla-drb10301-haplotype-in-ex-vivo-b-cells/. Accessed January 22, 2022.
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