Identification of a neutrophil-related gene expression signature that is enriched in adult systemic lupus erythematosus patients with active nephritis: Clinical/pathologic associations and etiologic mechanisms

PLoS One. 2018 May 9;13(5):e0196117. doi: 10.1371/journal.pone.0196117. eCollection 2018.

Abstract

Both a lack of biomarkers and relatively ineffective treatments constitute impediments to management of lupus nephritis (LN). Here we used gene expression microarrays to contrast the transcriptomic profiles of active SLE patients with and without LN to identify potential biomarkers for this condition. RNA isolated from whole peripheral blood of active SLE patients was used for transcriptomic profiling and the data analyzed by linear modeling, with corrections for multiple testing. Results were validated in a second cohort of SLE patients, using NanoString technology. The majority of genes demonstrating altered transcript abundance between patients with and without LN were neutrophil-related. Findings in the validation cohort confirmed this observation and showed that levels of RNA abundance in renal remission were similar to active patients without LN. In secondary analyses, RNA abundance correlated with disease activity, hematuria and proteinuria, but not renal biopsy changes. As abundance levels of the individual transcripts correlated strongly with each other, a composite neutrophil score was generated by summing all levels before examining additional correlations. There was a modest correlation between the neutrophil score and the blood neutrophil count, which was largely driven by the dose of glucocorticosteroids and not the proportion of low density and/or activated neutrophils. Analysis of longitudinal data revealed no correlation between baseline neutrophil score or changes over the first year of follow-up with subsequent renal flare or treatment outcomes, respectively. The findings argue that although the neutrophil score is associated with LN, its clinical utility as a biomarker may be limited.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Count
  • Female
  • Gene Expression Profiling*
  • Humans
  • Interferons / pharmacology
  • Lupus Nephritis / etiology
  • Lupus Nephritis / genetics*
  • Lupus Nephritis / immunology*
  • Male
  • Middle Aged
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Neutrophils / metabolism*
  • Young Adult

Substances

  • Interferons

Grants and funding

Dr. Landolt-Marticorena was the recipient of a Clinician-Scientist Salary Award from the Arthritis and Autoimmunity Research Centre of the University Health Network. Dr. Fortin was the recipient of a Distinguished Senior Investigator of The Arthritis Society and was supported by the Arthritis Centre of Excellence, University of Toronto. He is currently supported by a tenured Professorship of Medicine and a Canada Research Chair on systemic autoimmune rheumatic diseases at Université Laval. Dr. Reich’s work is supported by the Gabor Zellerman Chair in Nephrology Research at the University of Toronto. Dr. Boutros was supported by a CIHR New Investigator Award and has ongoing support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. Dr. Wither is funded by The Arthritis Centre of Excellence of the University of Toronto. The work outlined in this manuscript was partially supported by Eli Lilly Company who paid for the microarrays that were performed by Asurgen Services. The study was also partially funded by a New Emerging Team grant from the Canadian Institutes of Health Research (CIHR - QNT #78341). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.