title: Aberrant expression of shared master-key genes contributes to the immunopathogenesis in patients with juvenile spondyloarthritis.
abstract: Association of juvenile spondyloarthritis (jSpA) with the HLA-B27 genotype is well established, but there is little knowledge of other genetic factors with a role in the development of the disease. To date, only a few studies have tried to find those associated genes by obtaining expression profiles, but with inconsistent results due to various patient selection criteria and methodology. The aim of the present study was to identify and confirm gene signatures and novel biomarkers in highly homogeneous cohorts of untreated and treated patients diagnosed with jSpA and other forms of juvenile idiopathic arthritis (JIA) according to ILAR criteria. For the purposes of the research, total RNA was isolated from whole blood of 45 children with jSpA and known HLA genotype, 11 children with oligo- and polyarticular forms of JIA, as well as 12 age and sex matched control participants without diagnosis of inflammatory disease. DNA microarray gene expression was performed in 11 patients with jSpA and in four healthy controls, along with bioinformatical analysis of retrieved data. Carefully selected differentially expressed genes where analyzed by qRT-PCR in all participants of the study. Microarray results and bioinformatical analysis revealed 745 differentially expressed genes involved in various inflammatory processes, while qRT-PCR analysis of selected genes confirmed data universality and specificity of expression profiles in jSpA patients. The present study indicates that jSpA could be a polygenic disease with a possible malfunction in antigen recognition and activation of immunological response, migration of inflammatory cells and regulation of the immune system. Among genes involved in these processes TLR4, NLRP3, CXCR4 and PTPN12 showed almost consistent expression in study patients diagnosed with jSpA. Those genes and their products could therefore potentially be used as novel biomarkers, possibly predictive of disease prognosis and response to therapy, or even as a target for new therapeutic approaches.
authors.affiliation: Department of Pediatrics, University of Zagreb School of Medicine, Zagreb, Croatia; Division of Pediatric and Adolescent Rheumatology, Children's Hospital Srebrnjak, Zagreb, Croatia.
authors.forename: Lovro
authors.initials: L
authors.lastname: Lamot
authors.affiliation: Department for Functional Genomics, Center for Translational and Clinical Research, University of Zagreb School of Medicine, Zagreb, Croatia.
authors.forename: Fran
authors.initials: F
authors.lastname: Borovecki
authors.affiliation: Division of Pediatric and Adolescent Rheumatology, Children's Hospital Srebrnjak, Zagreb, Croatia.
authors.forename: Lana
authors.initials: L
authors.lastname: Tambic Bukovac
authors.affiliation: Division of Pediatric and Adolescent Rheumatology, Children's Hospital Srebrnjak, Zagreb, Croatia.
authors.forename: Mandica
authors.initials: M
authors.lastname: Vidovic
authors.affiliation: Division of Pediatric and Adolescent Rheumatology, Children's Hospital Srebrnjak, Zagreb, Croatia.
authors.forename: Marija
authors.initials: M
authors.lastname: Perica
authors.affiliation: Department for Functional Genomics, Center for Translational and Clinical Research, University of Zagreb School of Medicine, Zagreb, Croatia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Gotovac
authors.affiliation: Department of Pediatrics, University of Zagreb School of Medicine, Zagreb, Croatia; Division of Pediatric and Adolescent Rheumatology, Children's Hospital Srebrnjak, Zagreb, Croatia.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Harjacek
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000235:genetics* / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007962:Leukocytes / Q000276:immunology; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Q000235:genetics* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: C527276:CXCR4 protein, human; D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D019718:Receptors, CXCR4; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C516738:PTPN12 protein, human; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12