Τhe genetics of juvenile idiopathic arthritis: Searching for new susceptibility loci

Zervou,Maria I.; Dimopoulou,Despoina  G.; Eliopoulos,Elias; Trachana,Maria; Pratsidou‑Gkertsi,Polyxeni; Andreou,Athena; Sidiropoulos,Prodromos; Spandidos,Demetrios  A.; Garyfallos,Alexandros; Goulielmos,George  N.

doi:10.3892/mmr.2017.7733

Τhe genetics of juvenile idiopathic arthritis: Searching for new susceptibility loci

Authors:
- Maria I. Zervou
- Despoina G. Dimopoulou
- Elias Eliopoulos
- Maria Trachana
- Polyxeni Pratsidou‑Gkertsi
- Athena Andreou
- Prodromos Sidiropoulos
- Demetrios A. Spandidos
- Alexandros Garyfallos
- George N. Goulielmos
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Affiliations: Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion 71003, Greece, 4th Department of Internal Medicine, Hippocratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece, Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens 11855, Greece, 1st Department of Pediatrics, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece, Department of Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion 71500, Greece, Laboratory of Clinical Virology, School of Medicine, University of Crete, Heraklion 54124, Greece
Published online on: October 5, 2017 https://doi.org/10.3892/mmr.2017.7733
Pages: 8793-8798
Copyright: © Zervou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Juvenile idiopathic arthritis (JIA) is an autoimmune disease that is characterized by persistent chronic arthritis and affected by genetic and environmental factors. Different genetic variations have been reported as risk factors for JIA. However, given that many results could not be replicated in individuals of different ancestral origin, it was assumed that heterogeneous genetic factors are involved in this disease. In the present study, we analyzed three single nucleotide polymorphisms (SNPs), namely PTPRC (rs10919563), TYK2 (rs34536443) and PRKCQ (rs4750316), which were found to be associated with JIA in previous studies. We also investigated whether the intron‑4 located 27‑bp VNTR of endothelial nitric oxide synthase (eNOS), is associated with risk for JIA in Greece. In total, 125 JIA patients and 221 healthy controls from northern Greece were included in the study as a sample set. Samples were then analyzed, and genotyped for the three SNPs with TaqMan primer‑probe sets, using a Real‑Time PCR platform (ViiA™ 7 Real‑Time PCR system), while eNOS VNTR polymorphism was genotyped by PCR. Statistical analysis was performed using a GraphPad Prism statistical program. The χ2 test was used to examine differences of genotype and allele frequencies between patients and controls. Statistical significance was defined by using the two‑tailed P<0.05 test. Bioinformatics analysis was conducted by using BlastP, Pymol, Maestro and Desmond. In the case‑control association study performed, eNOS only was found to be associated with JIA. Genotype a/a and allele ‘a’ were found in a higher frequency in JIA patients than in controls [p<0.0001, odds ratio (OR)=0.15, 95% confidence intervals (CI): 0.065‑0.37; and p<0.0001, OR=0.34, 95% CI: 0.23‑0.49, respectively]. No associations with JIA were detected for TYK2, PTPRC or PRKCQ. Aiming to investigate the structural consequences and the structure/function relationships accompanying the Pro1104 to Ala (rs34536443) mutation on TYK2 protein, bioinformatics analysis was performed. Combining three‑dimensional (3D)‑modeling and molecular dynamics simulations we identified changes in structural flexibility, affecting the functionality of the kinase domain of TYK2. To the best of our knowledge, this is the first time that eNOS VNTR polymorphism is associated with susceptibility to JIA, suggesting a differential role of allele ‘a’ in various complex diseases. The current data emphasize the importance of comparative studies in populations of a different ancestral background towards the clarification of the role of specific alleles in the development of JIA.

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