Molecular signatures and new candidates to target the pathogenesis of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of unknown etiology and pronounced interpatient heterogeneity. To characterize RA at the molecular level and to uncover pathomechanisms, we performed genome-wide gene expression analysis. We identified a set of 1,054 genes significantly deregulated in pair-wise comparisons between RA and osteoarthritis (OA) patients, RA and normal donors (ND), or OA and ND. Correlation analysis revealed gene sets regulated identically in all three groups. As a prominent example secreted phosphoprotein 1 (SPP1) was identified to be significantly upregulated in RA compared with both OA and ND. SPP1 expression was found to correlate with genes expressed during an inflammatory response, T-cell activation and apoptosis, suggesting common underlying regulatory networks. A subclassification of RA patients was achieved on the basis of proteoglycan 4 (PRG4) expression, distinguishing PRG4 high and low expressors and reflecting the heterogeneity of the disease. In addition, we found that low PRG4 expression was associated with a more aggressive disease stage, which is in accordance with PRG4 loss-of-function mutations causing camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Altogether we provide evidence for molecular signatures of RA and RA subclasses, sets of new candidate genes as well as for candidate gene networks, which extend our understanding of disease mechanisms and may lead to an improved diagnosis.

[Functional genome analysis investigating resistance to respiratory tract disease in a porcine Actinobacillus pleuropneumoniae infection model]. / Funktionelle Genomanalyse zur Resistenz gegen Atemwegsinfektionen am Beispiel der Actinobacillus-Pleuropneumonie des Schweins.

Here we present the work of the multidisciplinary consortium IRAS (Development of Genetic Markers for Immune Defence and Resistance in the Porcine Respiratory Tract) which includes different commercial and research institutions and was formed as a response to the call "Functional Genome Analysis in the Animal Organism (FUGATO)" by the German Ministry of Education and Research. IRAS started work in the fall of 2005 and--using the experimental infection of pigs with Actinobacillus pleuropneumoniae as model pathogen--aims at i) characterizing the course of infection by clinical as well as advanced laboratory tools (phenotypic-genetic approach) and ii) defining the diversity and distribution of allels known to be associated with immune defence in mouse and man (homolog-genetic approach). The intention is to identify genetic markers for increased resistance to infection thereby providing additional tools for the estimation of breeding values to the pig industry.