Objectives Type I interferon (IFN) plays a role in the pathogenesis of systemic lupus erythematosus (SLE), but insufficient attention has been directed to the differences in IFN responses between ancestral populations. Here, we explored the expression of the interferon gene signatures (IGSs) in SLE patients of European ancestry (EA) and Asian ancestry (AsA).
Methods We used gene set variation analysis with multiple IGS encompassing the response to both type 1 and type 2 IFN in isolated CD14+ monocytes, CD19+B cells, CD4+T cells and Natural Killer (NK) cells from patients with SLE stratified by self-identified ancestry. The expression of genes upstream of the IGS and influenced by lupus-associated risk alleles was also examined. Lastly, we employed machine learning (ML) models to assess the most important features classifying patients by disease activity.
Results AsA patients with SLE exhibited greater enrichment in the IFN core and IFNA2 IGS compared with EA patients in all cell types examined and, in the presence and absence of autoantibodies. Overall, AsA patients with SLE demonstrated higher expression of genes upstream of the IGS than EA counterparts. ML with feature importance analysis indicated that IGS expression in NK cells, anti-dsDNA, complement levels and AsA status contributed to disease activity.
Conclusions AsA patients with SLE exhibited higher IGS than EA patients in all cell types regardless of autoantibody status, with enhanced expression of genetically associated genes upstream of the IGS potentially contributing. AsA, along with the IGS in NK cells, anti-dsDNA and complement, independently influenced SLE disease activity.
- Autoimmune Diseases
- Lupus Erythematosus, Systemic
- Polymorphism, Genetic
Data availability statement
Data are available in a public, open access repository.
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Contributors IR collected the data, performed the analyses and wrote the manuscript. KAO contributed data, performed analyses and wrote the manuscript. PB and EH contributed data and performed analyses. JY and MD’E collected and contributed data (CLUES dataset). ACG and PEL conceived and designed the analyses, supervised the work and wrote the manuscript. PEL is the guarantor, accpeting full responsibility for the conduct of the study.
Funding The work presented in this manuscript was funded by a Grant from the RILITE foundation. The funder provided support in the form of salaries for authors (IR, KAO and PB). Generation of data included in GSE164457 was supported by the Centers for Disease Control (5U01DP006486) to MDE and JY.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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