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Identifier 000419054
Title Μελέτη της επικάλυψης σε γενετικό επίπεδο μεταξύ των νοσημάτων της Ρευματοειδούς Αρθρίτιδας και της Ψωριασικής Αρθρίτιδας.
Alternative Title Study of the genetic overlap between the diseases of rheumatoid and psoriatic arthritis.
Author Μυρθιανού, Ευσεβία
Thesis advisor Γουλιέλμος, Γεώργιος
Reviewer Σιδηρόπουλος, Πρόδρομος
Καρδάσης, Δημήτριος
Σουρβίνος, Γεώργιος
Κρασαγάκης, Κωνσταντίνος
Μπερτσιάς, Γεώργιος
Κοφτερίδης, Διαμαντής
Abstract Rheumatoid arthritis (RA) is an autoimmune, inflammatory condition of the joints with a complex genetic background that affects more than 1% of the world's population. It has been extensively studied for several years and it has been revealed that most of the genetic predisposition for the disease is due to the HLA-DRB1 gene. In addition to this gene, many genes have been studied and we have now come to know that there are over 100 genetic loci contributing to the pathogenesis of the disease. Psoriatic arthritis (PsA) is also a complex disease characterized by chronic inflammatory arthritis in the presence of psoriasis. In particular, about 30% of patients with psoriasis develop psoriatic arthritis. The genetic background of the disease is very strong. The two diseases share many features. Patients respond to similar treatments and in addition, both are complex diseases that are associated with genetic and environmental risk factors. In recent years, great progress has been made in the field of discovering predisposition genes for RA. A significant observation is the pleiotropic effect of genes that are risk factors for RA. Most of these genes have been associated with the appearance of other autoimmune diseases, such as Type 1 Diabetes (T1D), Lupus (SLE), Psoriasis (PS), and Coeliac Disease. These autoimmune diseases are characterized by the presence of autoantibodies, as opposed to psoriatic arthritis that is seronegative. However, given the large overlap of clinical features and manifestations between RA and PsA, it is expected to overlap on the genetic background as well. For the above reason, various international research teams are conducting studies to clarify whether there is a common genetic background between the various diseases. The idea that there are genes that predispose to multiple autoimmune diseases has been around for many years. Indeed, both the HLA region and the PTPN22 and CTLA-4 genes are known to be associated with various diseases. One notable example is that almost all of the genetic loci associated with rheumatoid arthritis are also associated with juvenile idiopathic arthritis. In addition, a significant degree of overlap is present for the genes recognized for type I diabetes, with diseases such as celiac disease, Grave's disease (granulomatosis) and rheumatoid arthritis. Regarding psoriatic arthritis and its possible genetic overlap with rheumatoid arthritis, few studies have been undertaken so far. In a study published in March 2012, researchers attempted to analyze 54 polymorphisms in 41 genes, already known to predispose for rheumatoid arthritis, in a large group of patients of European origin with psoriatic arthritis. The results of the analysis showed strong correlation with the REL, PLCL2 and CCL21 genes. These first encouraging results have prompted us to investigate specific genes in a different ethnic population in order to gain insight in the issue of a potential genetic overlap between RA and PsA. The purpose of the current study was to investigate the possible existence of a shared genetic background, between the diseases of rheumatoid and psoriatic arthritis, in patients from the island of Crete, Greece. More specifically, we selected for our study polymorphisms in the PLCL2, CCL21, REL, STAT4, CD226, PTPN22 and TYK2 genes both in patients and healthy individuals. In the first part of the study, genotyping of patients and healthy individuals was performed and after statistical analysis at allelic and genotype level, conclusions were drawn for the correlation of the polymorphisms with the two diseases. In parallel, in the second part of the study, three-dimensional imaging methods were applied and bioinformatics tools were used to draw conclusions about the possible functional effects of some of the aforementioned polymorphisms. The results of the analysis showed that there is a significant genetic association between the GC genotype of rs34536443 (TYK2) with PsA but also with RA. The C allele of this SNP was associated with PsA only. We also found correlation data with PsA for the GG genotype and the G allele of the STAT4 gene (rs10181656 polymorphism). In addition, the TC genotype of the rs763361 polymorphism of the CD226 gene was only associated with PsA but not with RA. The frequencies of the 1858C / T alleles of the PTPN22 gene did not show significant difference between rheumatoid arthritis patients and healthy subjects, although the minor allele T was found to be more frequent in healthy individuals than in patients with psoriatic arthritis. However, the difference observed was not statistically significant. One interesting observation was that none of the three remaining polymorphisms that we studied [rs4535211 (PLCL2), rs2812378 (CCL21) and rs13017599 (REL)] were found to be associated with rheumatoid or psoriatic arthritis. In an attempt to investigate the functional implications of these findings, we tested the polymorphism in TYK2 by using bioinformatics tools. The nucleotide substitution probably alters the tertiary structure of the TYK2 protein and affects the folding and interaction parameters of the molecule, thus resulting in changes regarding its functionality. As regards with the STAT4 gene polymorphism, analysis of the polymorphism-based sequence revealed that the major C allele rather than the minor G allele contributes to the creation of a potential binding site for the transcription factors Pax-4, PPAR / RXR and ZNF99. Thus, it can be hypothesized that the minor allele of rs10181656, which was found to have an increased frequency in PsA, may suppress Tcell activation through the disturbance of the binding of the PPARα/RXRα dimer. For the CD226 gene polymorphism, we analyzed in detail the existing 3D models of this protein and we propose that the Ser307 residue is most likely to be involved in polar interactions associated with proximal charged residues or phosphorylation sites. By affecting the proximal phosphorylation sites or protein–protein subunit recognition, this mutation could alter the signaling cascade. The different findings of the current study in comparison to previous ones highlights the importance of comparative studies that include different ethnic or racial populations, in any attempt to confirm genetic associations detected.
Language Greek
Subject Genes
Issue date 2018-12-05
Collection   Faculty/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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