Genetic susceptibility loci in rheumatoid arthritis establish transcriptional regulatory networks with other genes.
Linkage studies have identified the human leukocyte antigen (HLA)-DRB1 as a putative rheumatoid arthritis (RA) susceptibility locus (SL). Nevertheless, it was estimated that its contribution was partial, suggesting that other non-HLA genes may play a role in RA susceptibility. To test this hypothesis, we conducted microarray transcription profiling of peripheral blood mononuclear cells in 15 RA patients and analyzed the data, using bioinformatics programs (significance analysis of microarrays method and GeneNetwork), which allowed us to determine the differentially expressed genes and to reconstruct transcriptional networks. The patients were grouped according to disease features or treatment with tumor necrosis factor blocker. Transcriptional networks that were reconstructed allowed us to identify the interactions occurring between RA SL and other genes, for example, HLA-DRB1 interacting with FNDC3A (fibronectin type III domain containing 3A). Given that fibronectin fragments can stimulate mediators of matrix and cartilage destruction in RA, this interaction is of special interest and may contribute to a clearer understanding of the functional role of HLA-DRB1 in RA pathogenesis.
Silva
Guilherme Liberato
GL
Molecular Immunogenetics Group, Department of Genetics, University of São Paulo, Ribeirão Preto, Brazil.
Junta
Cristina Moraes
CM
Sakamoto-Hojo
Elza Tiemi
ET
Donadi
Eduardo Antonio
EA
Louzada-Junior
Paulo
P
Passos
Geraldo A S
GA
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010456:Peptides, Cyclic / Q000276:immunology
D001323:Autoantibodies; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide