| Background Rheumatoid arthritis(RA) is a chronic systemic autoimmune disease characterized by persistent synovitis, systemic inflammation, and autoantibodies(particularly to rheumatoid factor and citrullinated peptide), which can eventually cause pain, joint deformation and disability. The prevalence of rheumatoid arthritis is about 1% in adult population of the world. Now, the exact pathogenesis of RA was unclear. The causes of RA are varied. Studies have suggested that RA may be related to the genetic factors, the destruction of the immune tolerance, infection factors, endocrine abnormalities and their interactions, which causing adaptive immunity and natural immune disorders. In recent years, to explore the pathogenesis of RA from the genetic perspective is becoming a hot spot of related research. Genome-wide association and candidate gene studies have identified more than 50 genetic regions associated with RA. In addition family aggregation and twin studies have revealed that genetic factors are major determinants of the susceptibility to RA.In recent years, Ubiquitin-associated and SH3 domain-containing protein A(UBASH3A) is a member of the Protein tyrosine phosphatases(PTPs) family, also referred to as T-cell Ubiquitin Lig And(TULA) or Suppressor of T-cell Signaling 2(STS-2). UBASH3 A genes mainly expressed in kidney, spleen, lung and lymph cells. UBASH3 A protein amino acid sequences contain N-terminal and ubiquitin associated structure, intermediate Src homology 3(SH3) domains and the phosphoglycerate mutase(PGM) domain of C-terminal(Fig 1). UBASH3 A act as a negative regulator of T cell receptor mediated signaling pathways(T cell receptor, TCR), which plays an important role in the regulation of immune response. Several previous studies have reported that UBASH3A was associated with susceptibility to autoimmune diseases such as systemic lupus erythematosus(SLE), RA and Graves’ disease(GD).Currently, there is limited research about UBASH3 A involved in the pathogenesis of RA. Especially in the Chinese population, the associations between UBASH3 A polymorphisms, m RNA expression and RA are unclear. Thus, our study adopted a case-control study to explore the association between UBASH3 A gene polymorphism, m RNA expression and RA. We also analyzed the relationship between m RNA expression and polymorphism of the UBASH3 A gene, and the main clinical and laboratory features in RA.Fig 1 schematic view of UBASH3 A protein structurePartⅠAssociation Study of UBASH3 A Polymorphisms with Rheumatoid ArthritisObjective To explore UBASH3A(SNPs rs1893592, rs2277798 and rs11203203) whether or not confer susceptibility to RA, and to investigate association between the polymorphisms and the main clinical and laboratory features in RA.Methods A total of 557 patients with RA and 954 healthy controls were included. All patientsfulfilled the 1987 revised criteria of the American College of Rheumatology for the classification of RA. Demographic data and clinical data were collected by questionnaire. EDTA anti-coagulated venous blood samples were collected from all participants. Genomic DNA was extracted from peripheral blood lymphocytes. Fluidigm 192.24 Dynamic Array and Taq Man probe genotyping detection methods were used to analysis three loci of UBASH3 A gene. Statistical analysis was performed using SPSS 11.0 software. The probability level as <0.05 in two-tailed test was considered statistically significant.Results(1) No deviations from HWE were observed in the controls in each polymorphism.(For SNP rs1893592, χ2=1.454,P=0.228; For SNP rs2277798, χ2=1.217,P=0.270; For SNP rs11203203, χ2=1.347,P=0.246)(2) The allele and genotype frequencies of rs1893592 were statistically significant different between cases and controls(A versus C:χ2=19.187,P<0.001,OR=1.470,95%CI:1.237-1.748; AA+AC versus CC: χ2=11.119,P=0.001,OR=2.419,95%CI:1.439-4.066; AA versus AC+CC: χ2=7.815,P=0.005,OR=1.394,95%CI:1.104-1.760). While the allele and genotype frequencies of rs2277798 and rs11203203 were not statistically significant different between cases and controls(P>0.05).(3) The genotype frequencies of rs11203203 were statistically significant different between RF-positive RA cases and RF-negative RA cases(P=0.011). The data showed that increased frequencies of G allele(rs2277798) in patients with anti-CCP-positive as compared with anti-CCP-negative(P=0.018, OR=1.642, 95%CI: 1.084-2.434). We did not find association of clinical features with rs1893592 in RA patients(P>0.05).Conclusions UBASH3 A gene rs1893592 polymorphism is associated with the susceptibility to RA patients in Chinese Han population; rs11203203 polymorphism may be associated with RA patients who combined with positive of RF; rs2277798 polymorphism may be correlated with RA patients who merged with Anti-CCP positive. The findings suggest that UBASH3 A gene might contribute to RA susceptibility and influence the clinical phenotype of the disease.PartⅡAssociation Study of UBASH3 A m RNA Expression with Rheumatoid ArthritisObjective To compare the expression of UBASH3 A m RNA in RA patients and healthy controls. Combined with clinical and laboratory data, the relationship with their m RNA levels were further analyzed. And the association between the UBASH3 A gene and m RNA expression in RA patients was analyzed.Methods A total of 30 patients with SLE and 31 controls were selected from samples of PartⅠ. Demographic data and clinical data were collected by questionnaire. EDTA anti-coagulated venous blood samples were collected from all participants and total RNA was extracted. The lever of m RNA expression in PBMC was detected by relative quantitation PCR. The nonparametric Mann-Whitney U two sample tests were used to comparing the median between different groups. For the correlation analysis between UBASH3 A m RNA and clinical features, Spearman’s rank correlation coefficient was used. Statistical analysis was performed using SPSS 11.0 software. The probability level as <0.05 in two-tailed test was considered statistically significant.Results(1) UBASH3 A m RNA expressions in PBMCs were decreased in RA patients compared with healthy controls(P=0.001). The expression level of UBASH3 A m RNA in the different active groups and remission group showed no significant difference(P>0.05).(2) Expression level of UBASH3 A m RNA in RF-positive RA groups and in RF-negative RA groups showed no significant difference(P=0.670). The expression level of UBASH3 A m RNA in CCP-positive RA groups and CCP-negative RA groups showed no significant difference(P=0.353).(3) Our results showed that there is no significant difference between UBASH3 A m RNA expression and other laboratory features such as ESR, CRP, course of disease, age of onset and DAS28(P>0.05).(4) We analyzed UBASH3 A gene(rs1893592, rs2277798 and rs11203203) polymorphisms with UBASH3 A m RNA expression among RA patients. There is no significant difference between genotypes of the three SNPs and m RNA expression(P>0.05).Conclusions In summary, UBASH3 A m RNA expressions were lower in RA patients than the healthy controls. But, no association was found between the UBASH3 A gene m RNA expression and UBASH3 A gene and the major clinical clinical features. The decreased expression level of UBASH3 A m RNA in RA patients suggested that UBASH3 A may involve in the pathogenesis of RA. |
PDF Full Text Request