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.
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