Rheumatoid Arthritis subtypes identified by genomic profiling of peripheral blood cells: Assignment of a type I interferon signature in a subpopulation of patients

T CTM van der Pouw Kraan ¹, C A Wijbrandts ², L GM van Baarsen ¹, A E Voskuyl ¹, F Rustenburg ¹, J M Baggen ¹, S M Ibrahim ³, M Fero ⁴, B AC Dijkmans ¹, P-P Tak ² and C L Verweij ^1*

¹ VUmc, Netherlands
² AMC, Netherlands
³ University of Rostock, Germany
⁴ Stanford Functional Genomics Facility, United States

^* To whom correspondence should be addressed. E-mail: c.verweij{at}vumc.nl.

Accepted 16 December 2006

Abstract

Objective: Rheumatoid arthritis (RA) is a heterogeneous disease with unknown etiology. Here we aimed to identify peripheral blood gene expression profiles that may distinguish RA subtypes.

Methods: Large-scale expression profiling by cDNA microarrays was performed on peripheral blood from 35 patients and 15 healthy individuals. Differential gene expression was analyzed by Significance Analysis of Microarrays (SAM), followed by Gene Ontology analysis of the significant genes. Gene Set Enrichment Analysis (GSEA) was applied to identify pathways relevant to disease.

Results: We found a remarkably elevated expression of a spectrum of genes involved in immune defense in the peripheral blood of RA patients compared to healthy individuals. SAM analysis revealed a highly significant elevated expression of interferon (IFN) type I regulated genes in RA compared to healthy individuals, which was confirmed by Gene Ontology and Pathway analysis, suggesting that this pathway was activated systemically in RA. A quantitative analysis revealed that increased expression of IFN-response genes was characteristic of approximately half of the patients (IFN^high patients). Application of pathway analysis revealed that the IFN^high group was largely different from the controls, with evidence for upregulated pathways involved in coagulation and complement cascades, and fatty acid metabolism, while the IFNlow group was similar to the controls.

Conclusion: The IFN type I signature defines a subgroup of RA patients, with a distinct biomolecular phenotype, characterized by increased activity of the innate defense system.

Keywords: Interferon Type I, autoimmune Diseases, blood cells, classification, gene Expression Profiling

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