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

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.

WITHDRAWN: Target region sequencing and gene polymorphism of Chinese Uyghur individuals with autoimmune thyroid diseases (AITDs)

“…PTPRC (CD45) is a protein coding gene, which can encode a member of the protein tyrosine phosphatase (PTP) family. So far, even though the role of PTPRC gene plays in the AITDs is not very clear, but the genetic variations of PTPRC have been reported as risk factors for another autoimmune disease, Juvenile idiopathic arthritis (JIA) [38]. Above mentioned SNPs harboring AITDs susceptibility genes we have identified have not been reported in other researches before, suggesting AITDs Uyghur patients could be more likely to owe their special genetic characteristics.…”

The Multi-Omics Architecture of Juvenile Idiopathic Arthritis

“…Zervou et al investigated the nonsynonymous SNP rs34536443 on TYK2 [ 82 ], which has been shown of association with various rheumatic diseases. The SNP results in amino acid substitution of Pro1104 to Ala.…”

“…The SNP results in amino acid substitution of Pro1104 to Ala. The study found that the SNP led to the extension of the α-helical segment and alternation of the protein 3D structure, which is likely to affect the function of the TYK2 protein [ 82 ]. Couturier et al performed a study on the association between TYK2 polymorphism and multiple sclerosis in 1366 French patients and 1802 matched controls [ 83 ].…”

Association of TYK2 rs34536443 polymorphism with Susceptibility to Systemic Lupus Erythematous in the Iranian Population

“…Peluso et al reported decreased susceptibility to ERI in Brazilian women due to the C allele of TYK2 rs34536443 polymorphism [11]. Zervou et al found no significant association between the rs34536443 variant and JIA in the Greek population at either the genotype or allelic levels [45]. Diogo et al demonstrated that allele C of rs34536443 protects against inflammatory bowel disease (IBD), RA and SLE [44], while others demonstrated that the allele is a risk factor for psoriasis [46] and JIA [47].…”