Functional Variants Of TNFAIP3 Are Associated With Systemic Lupus Erythematosus In A Cohort Of Chinese Han Population

Systemic lupus erythematosus?SLE?is an autoimmune disease characterized by self-reactive antibodies production resulting in systemic inflammation and target organs failure.Tumor necrosis factor-alpha-induced protein 3?TNFAIP3?has been detected in several cell types of immune system,verified to inhibit NF-?B activity by deubiquitinating-specific NF-?B signal pathways.We can already be aware of the fact that the tandem polymorphic dinucleotide of TNFAIP3,TT>A?rs148314165,rs200820567?associated with the risk for SLE in European and Korean populations through the previous studies.However,it'still unclear whether the TT>A variants are present in Chinese Han population and its association with SLE susceptibility.The purpose of this study was to investigate the association between TNFAIP3gene mutations and susceptibility to SLE in our cohort of Chinese Han population,and to further investigate the effects of this disease on the expression of TNFAIP3mRNA and NF-?B activity.Methods are as follows:we have gathered 1229 Chinese Han SLE patients samples and 1608 matched healthy controls,The two SNPs,rs148314165 and rs200820567 were genotyped by Sanger Sequencing and Taqman SNP genotyping assay,the results were obtained by linkage disequilibrium analysis to determine the degree of association with SLE susceptibility.The expression levels of TNFAIP3 gene and NF-?B in PBMCs from patients and healthy controls were evaluated using real-time PCR,and their association with TT>A were detected.We proceeded to investigate the genetic association of the TT>A variants likewise the functional coding variant rs2230926 in exon 3 of TNFAIP3.We further explored the effect of those variants in NF-?B signaling and the expression of the TNFAIP3 gene under regulation in their peripheral blood mononuclear cells?PBMCs?from Chinese SLE patients.According to the results,those TT>A variants and rs2230926,the TNFAIP3exon 3 coding variant demonstrated remarkable associations in Chinese Han SLE patients selected(P_TT>A=8.96×10^-12,odds ratio[OR]=2.07,95%confidence interval[CI]=1.68–2.55).This group of patients carrying the risk A allele revealed decreased mRNA expression of the TNFAIP3 gene meanwhile increased expression of NF-?B1 in PBMCs.Conditional analyses showed that the TT>A variants are potentially to be causal variants in Chinese Han SLE patients.The results above showed that the TT>A variants associated with Chinese Han SLE and was a negative regulator of the expression of the TNFAIP3 gene leading to enhanced NF-?B activity.