Transcription of proteinase 3 and related myelopoiesis genes in peripheral blood mononuclear cells of patients with active Wegener's granulomatosis.

Abstract

OBJECTIVE:

Wegener's granulomatosis (WG) is a systemic inflammatory disease that is associated with substantial morbidity. The aim of this study was to understand the biology underlying WG and to discover markers of disease activity that would be useful for prognosis and treatment guidance.

METHODS:

Gene expression profiling was performed using total RNA from peripheral blood mononuclear cells (PBMCs) and granulocyte fractions from 41 patients with WG and 23 healthy control subjects. Gene set enrichment analysis (GSEA) was performed to search for candidate WG-associated molecular pathways and disease activity biomarkers. Principal components analysis was used to visualize relationships between subgroups of WG patients and controls. Longitudinal changes in proteinase 3 (PR3) gene expression were evaluated using reverse transcription-polymerase chain reaction, and clinical outcomes, including remission status and disease activity, were determined using the Birmingham Vasculitis Activity Score for WG (BVAS-WG).

RESULTS:

Eighty-six genes in WG PBMCs and 40 in WG polymorphonuclear neutrophils (PMNs) were significantly up-regulated relative to controls. Genes up-regulated in WG PBMCs were involved in myeloid differentiation, and these included the WG autoantigen PR3. The coordinated regulation of myeloid differentiation genes was confirmed by GSEA. The median expression values of the 86 up-regulated genes in WG PBMCs were associated with disease activity (P = 1.3 x 10(-4)), and WG patients with low-level expression of the WG signature genes showed expression profiles that were only modestly different from that in healthy controls (P = 0.07). PR3 transcription was significantly up-regulated in WG PBMCs (P = 1.3 x 10(-5), false discovery rate [FDR] 0.002), but not in WG PMNs (P = 0.03, FDR 0.28), and a preliminary longitudinal analysis showed that the fold change in PR3 RNA levels in WG PBMCs corresponded to changes in the BVAS-WG score over time.

CONCLUSION:

Transcription of PR3 and related myeloid differentiation genes in PBMCs may represent novel markers of disease activity in WG.

• Authors: Chris Cheadle, Alan E Berger, Felipe Andrade, Regina James, Kristen Johnson, Tonya Watkins, Jin Kyun Park, Yu-Chi Chen, Eva Ehrlich, Marissa Mullins, Francis Chrest, Kathleen C Barnes, Stuart M Levine
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 62 Issue 6 Pg. 1744-54 (Jun 2010) ISSN: 1529-0131 [Electronic] United States
• PMID: 20155833 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• RNA, Messenger
• Myeloblastin

Topics

• Adult
• Aged
• Autoantibodies (genetics, metabolism)
• Female
• Gene Expression Profiling
• Granulomatosis with Polyangiitis (genetics, metabolism)
• Humans
• Leukocytes, Mononuclear (metabolism)
• Male
• Middle Aged
• Myeloblastin (genetics, metabolism)
• Myelopoiesis (genetics)
• Oligonucleotide Array Sequence Analysis
• Principal Component Analysis
• RNA, Messenger (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Severity of Illness Index
• Transcription, Genetic (genetics)