Microarray-based gene expression profiling in patients with cryopyrin-associated periodic syndromes defines a disease-related signature and IL-1-responsive transcripts

Ann Rheum Dis. 2013 Jun;72(6):1064-70. doi: 10.1136/annrheumdis-2012-202082. Epub 2012 Dec 5.

Abstract

Objective: To analyse gene expression patterns and to define a specific gene expression signature in patients with the severe end of the spectrum of cryopyrin-associated periodic syndromes (CAPS). The molecular consequences of interleukin 1 inhibition were examined by comparing gene expression patterns in 16 CAPS patients before and after treatment with anakinra.

Methods: We collected peripheral blood mononuclear cells from 22 CAPS patients with active disease and from 14 healthy children. Transcripts that passed stringent filtering criteria (p values≤false discovery rate 1%) were considered as differentially expressed genes (DEG). A set of DEG was validated by quantitative reverse transcription PCR and functional studies with primary cells from CAPS patients and healthy controls. We used 17 CAPS and 66 non-CAPS patient samples to create a set of gene expression models that differentiates CAPS patients from controls and from patients with other autoinflammatory conditions.

Results: Many DEG include transcripts related to the regulation of innate and adaptive immune responses, oxidative stress, cell death, cell adhesion and motility. A set of gene expression-based models comprising the CAPS-specific gene expression signature correctly classified all 17 samples from an independent dataset. This classifier also correctly identified 15 of 16 post-anakinra CAPS samples despite the fact that these CAPS patients were in clinical remission.

Conclusions: We identified a gene expression signature that clearly distinguished CAPS patients from controls. A number of DEG were in common with other systemic inflammatory diseases such as systemic onset juvenile idiopathic arthritis. The CAPS-specific gene expression classifiers also suggest incomplete suppression of inflammation at low doses of anakinra.

Keywords: Cytokines; Fever Syndromes; Inflammation.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Antirheumatic Agents / therapeutic use*
  • Case-Control Studies
  • Child
  • Cryopyrin-Associated Periodic Syndromes / drug therapy
  • Cryopyrin-Associated Periodic Syndromes / genetics*
  • Gene Expression Profiling
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use*
  • Microarray Analysis
  • Models, Genetic
  • Severity of Illness Index
  • Transcriptome / drug effects
  • Transcriptome / genetics*

Substances

  • Antirheumatic Agents
  • Interleukin 1 Receptor Antagonist Protein