Correlation analyses of clinical and molecular findings identify candidate biological pathways in systemic juvenile idiopathic arthritis

Authors

Xuefeng B. Ling, Department of Surgery, Stanford UniversityFollow
Claudia Macaubas, Program in Immunology, Department of Pediatrics, Stanford UniversityFollow
Heather C. Alexander, Celera CorporationFollow
Qiaojun Wen, Department of Surgery, Stanford UniversityFollow
Edward Chen, Department of Surgery, Stanford UniversityFollow
Sihua Peng, Department of Surgery, Stanford UniversityFollow
Yue Sun, Program in Immunology, Department of Pediatrics, Stanford UniversityFollow
Chetan Deshpande, Program in Immunology, Department of Pediatrics, Stanford UniversityFollow
Kuang-Hung Pan, Department of Genetics, StanfordFollow
Richard Lin, Department of Genetics, StanfordFollow
Chih-Jian Lih, Department of Genetics, StanfordFollow
Sheng-Yung P. Chang, Celera CorporationFollow
Tzielan Lee, Division of Pediatric Rheumatology, Department of Pediatrics, Stanford UniversityFollow
Christy Sandborg, Division of Pediatric Rheumatology, Department of Pediatrics, Stanford UniversityFollow
Ann B. Begovich, Celera CorporationFollow
Stanley N. Cohen, Department of GeneticsFollow
Elizabeth D. Mellins, Program in Immunology, Department of Pediatrics, Stanford UniversityFollow

Document Type

Article

Abstract

Abstract

Background

Clinicians have long appreciated the distinct phenotype of systemic juvenile idiopathic arthritis (SJIA) compared to polyarticular juvenile idiopathic arthritis (POLY). We hypothesized that gene expression profiles of peripheral blood mononuclear cells (PBMC) from children with each disease would reveal distinct biological pathways when analyzed for significant associations with elevations in two markers of JIA activity, erythrocyte sedimentation rate (ESR) and number of affected joints (joint count, JC).

Methods

PBMC RNA from SJIA and POLY patients was profiled by kinetic PCR to analyze expression of 181 genes, selected for relevance to immune response pathways. Pearson correlation and Student's t-test analyses were performed to identify transcripts significantly associated with clinical parameters (ESR and JC) in SJIA or POLY samples. These transcripts were used to find related biological pathways.

Results

Combining Pearson and t-test analyses, we found 91 ESR-related and 92 JC-related genes in SJIA. For POLY, 20 ESR-related and 0 JC-related genes were found. Using Ingenuity Systems Pathways Analysis, we identified SJIA ESR-related and JC-related pathways. The two sets of pathways are strongly correlated. In contrast, there is a weaker correlation between SJIA and POLY ESR-related pathways. Notably, distinct biological processes were found to correlate with JC in samples from the earlier systemic plus arthritic phase (SAF) of SJIA compared to samples from the later arthritis-predominant phase (AF). Within the SJIA SAF group, IL-10 expression was related to JC, whereas lack of IL-4 appeared to characterize the chronic arthritis (AF) subgroup.

Conclusions

The strong correlation between pathways implicated in elevations of both ESR and JC in SJIA argues that the systemic and arthritic components of the disease are related mechanistically. Inflammatory pathways in SJIA are distinct from those in POLY course JIA, consistent with differences in clinically appreciated target organs. The limited number of ESR-related SJIA genes that also are associated with elevations of ESR in POLY implies that the SJIA associations are specific for SJIA, at least to some degree. The distinct pathways associated with arthritis in early and late SJIA raise the possibility that different immunobiology underlies arthritis over the course of SJIA.

Recommended Citation

Ling et al.: Correlation analyses of clinical and molecular findings identify candidate biological pathways in systemic juvenile idiopathic arthritis. BMC Medicine 2012 10:125.