Background Juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by persistent chronic arthritis, in which both genetic and environmental components are involved . Different genetic variations have been reported as risk factors for JIA, but a difficulty of the replication of results in different ethnic backgrounds indicates the existence of an ethnic heterogeneity of genetic factors for JIA.
Objectives We sought to validate three single nucleotide polymorphisms (SNPs), namely PTPRC (rs10919563), TYK2 (rs34536443) and PRKCQ (rs4750316), previously found to be associated with JIA [2–4], and to investigate whether the 27-bp VNTR polymorphism on intron 4 of eNOS, which is associated with various autoimmune diseases so far , is associated with risk for JIA in Greece.
Methods The sample set consisted of 125 JIA patients and 221 healthy controls from Northern Greece. Genotyping of the three SNPs was performed with Taqman primer-probe sets, using a Real-Time PCR platform (Applied Biosystems, ViiA™ 7 Real-Time PCR System), while eNOS VNTR polymorphism was genotyped by PCR. Odds ratios (OR) and 95% confidence intervals (CI) were calculated and the statistical difference in allele distribution was assessed by means of x2 test or Fisher's exact test. Bioinformatic analysis was performed using BlastP, Pymol and Maestro and Desmond (Schrodinger Inc.).
Results A case–control association study was conducted enrolling 4 successfully genotyped markers. eNOS only was found to be associated with JIA. Genotype a/a and allele “a” were more common in individuals with JIA than in controls (p<0.0001, OR=0.15, 95% 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 3D-modeling and Molecular Dynamics simulations we have noted changes in structural flexibility, affecting the functionality of the kinase domain of TYK2.
Conclusions This study demonstrated for the first time that eNOS VNTR polymorphism is associated with susceptibility to JIA, thus suggesting that the risk allele “a” may confer susceptibility to clinically distinct disorders. Apart from the previously reported evidence for the role of PTPRC rs10919563, PRKCQ rs4750316 and TYK2 rs34536443 in an increased risk for JIA, our results demonstrate no association of these genes with JIA in the Greek population. However, the lack of association of PTPRC SNP with JIA is in line with previous data reported from cohorts in US and Australia. Taken together, the results highlight the importance of comparative studies in different populations, considering that replication of previously identified markers is paramount to determine which SNPs represent true risk loci, thus pointing towards key disease pathways which warrant further study.
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Disclosure of Interest None declared