Identification of intra-group, inter-individual, and gene-specific variances in mRNA expression profiles in the rheumatoid arthritis synovial membrane.
BACKGROUND
Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease characterized by overexpression of pro-inflammatory/pro-destructive genes and other activating genes (for example, proto-oncogenes) in the synovial membrane (SM). The gene expression in disease is often characterized by significant inter-individual variances via specific synchronization/desynchronization of gene expression. To elucidate the contribution of the variance to the pathogenesis of disease, expression variances were tested in SM samples of RA patients, osteoarthritis (OA) patients, and normal controls (NCs).


METHODS
Analysis of gene expression in RA, OA, and NC samples was carried out using Affymetrix U133A/B oligonucleotide arrays, and the results were validated by real-time reverse transcription-polymerase chain reaction. For the comparison between RA and NC, 568 genes with significantly different variances in the two groups (P <or= 0.05; Bonferroni/Holm corrected Brown-Forsythe version of the Levene test) were selected. For the comparison between RA and OA, 333 genes were selected. By means of the Kyoto Encyclopedia of Genes and Genomes, the pathways/complexes significantly affected by higher gene expression variances were identified in each group.


RESULTS
Ten pathways/complexes significantly affected by higher gene expression variances were identified in RA compared with NC, including cytokine-cytokine receptor interactions, the transforming growth factor-beta pathway, and anti-apoptosis. Compared with OA, three pathways with significantly higher variances were identified in RA (for example, B-cell receptor signaling and vascular endothelial growth factor signaling). Functionally, the majority of the identified pathways are involved in the regulation of inflammation, proliferation, cell survival, and angiogenesis.


CONCLUSIONS
In RA, a number of disease-relevant or even disease-specific pathways/complexes are characterized by broad intra-group inter-individual expression variances. Thus, RA pathogenesis in different individuals may depend to a lesser extent on common alterations of the expression of specific key genes, and rather on individual-specific alterations of different genes resulting in common disturbances of key pathways.
Huber
René
R
Department of Orthopedics, Experimental Rheumatology Unit, University Hospital Jena, Waldkrankenhaus Rudolf Elle, Eisenberg, Germany.
Hummert
Christian
C
Gausmann
Ulrike
U
Pohlers
Dirk
D
Koczan
Dirk
D
Guthke
Reinhard
R
Kinne
Raimund W
RW
D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D002470:Cell Survival / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics; D010003:Osteoarthritis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013583:Synovial Membrane / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A