A GENOMIC VIEW ON RHEUMATIC DISEASES: DISCOVERY OF DISTINCTIVE GENE EXPRESSION PROFILES IN HUMAN ARTHRITIDES BY CDNA MICRO-ARRAY ANALYSIS

C. Verweij , T.C.T.M. Van der Pouw Kraan , F.A. Van Gaalen , A.A. Alizadeh , M. Fero , T.W.J. Huizinga , E. Pieterman , F.C. Breedveld , L.M. Staudt , D. Botstein , P.O. Brown Molecular Cell Biology, VUmc, Amsterdam, Rheumatology, LUMC, Leiden, Netherlands, Biochemistry/Howard Hughes Medical Institute, Genetics, Stanford University, Stanford, Clinical Sciences, NIH, Bethesda, USAA potentially powerful way to gain insight in the complex pathogenesis of rheumatoid arthritis (RA) and to classify arthritides has arisen from cDNA microarray technology, which provides the opportunity to determine differences in gene expression of a large portion of the genome in search of genes that are differently expressed between clinically diagnosed arthritides. Therefore, we studied the gene expression profile of synovial tissues from affected joints of patients with diagnosed RA (n=21) in comparison to those of patients with osteoarthritis (OA) (n=9). Cy-5 labeled mRNAs from these samples were hybridized together with a Cy-3 labeled common reference mRNA preparation to arrays containing approximately 18,000 genes of importance in immunology. Hierarchical cluster analysis of the genes that differed at least two-fold in at least 4 samples relative to the median Cy5 to Cy3 ratio, revealed a remarkably ordered variation in gene expression profiles in the affected joint tissues of patients with RA and OA.Based on the molecular signatures distinct subsets of RA tissues could be identified. One class showed abundant expression of clusters of genes indicative for an activation of the adaptive immune response, with high expression of eg. immunoglobulins, chemokine receptors and chemokines explaining the infiltration of T-, B cells and monocytes, genes involved in signalling and transcriptional activation, and genes not previously associated with RA. Significance analysis of microarray data (SAM) revealed a total of 165 independent cDNA sequences (including 74 ESTs) that significantly differed at least two-fold between these inflammatory RA tissues (n=9) and OA tissues. The other group of RA tissues resembled the expression pattern of the OA tissues, which is characterized by a low inflammatory gene expression signature and increased tissue remodeling activity. SAM analysis did not show significant differences in gene expression between the OA tissues and this subgroup of RA tissues.Conclusively, the differences in the gene expression profiles reveal molecular criteria to identify distinct subtypes of disease not recognized by current classification methods. Moreover, this information clearly shows the expression of novel genes and biological pathways involved in disease that may provide insight in the biological dysregulation underlying RA and OA.Citation: , volume , supplement , year 2002, page Session: Review Session – Update on genomics for clinicians: What does a clinician need to know about genomics?