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  • Differential regulation of the interferon response in systemic lupus erythematosus distinguishes patients of Asian ancestry

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Lupus
Original research
Differential regulation of the interferon response in systemic lupus erythematosus distinguishes patients of Asian ancestry
  1. Ian Rector1,
  2. Katherine A Owen2,
  3. Prathyusha Bachali1,
  4. Erika Hubbard1,
  5. Jinoos Yazdany3,
  6. Maria Dall'era4,
  7. Amrie C Grammer1 and
  8. Peter E Lipsky1
  1. 1AMPEL Biosolutions LLC and the RILITE Research Institute, Charlottesville, Virginia, USA
  2. 2AMPEL BioSolutions LLC, Charlottesville, Virginia, USA
  3. 3Medicine/Rheumatology, University of California, San Francisco, California, USA
  4. 4Division of Rheumatology, University of California, San Francisco, California, USA
  1. Correspondence to Dr Katherine A Owen; kate.owen{at}ampelbiosolutions.com

Abstract

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.

  • Autoantibodies
  • Autoimmune Diseases
  • Lupus Erythematosus, Systemic
  • Polymorphism, Genetic

Data availability statement

Data are available in a public, open access repository.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

http://dx.doi.org/10.1136/rmdopen-2023-003475

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    Data availability statement

    Data are available in a public, open access repository.

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    Footnotes

    • 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.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.