Association Of TNIP1/TNFAIP3with Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by theformation of autoantibodies and immune complex. The symptoms of disease include skinlesions and disorders of multiple organs such as the joints, kidneys, heart, liver, andcentral nervous system. The pathogenesis of SLE is not entirely clear, but genetics andenvironmental factors play important roles. Genetic analysis indicates non-Mendelianinheritance, with multiple SLE susceptibility genes.There exist in interactions betweenthese genes, and interactions between these genes and environmental factors. Several recentgenome-wide association studies (GWAS) have identified multiple SLE susceptibility genes.Two genes appear to play particularly important roles in the regulation of the autoimmuneinflammatory response in SLE:(i) TNFAIP3(tumor necrosis factor α-l induced protein3),which codes for the protein A20, and (ii) TNIP1(TNFAIP3interacting protein-1), whichcodes for the protein ABIN1(A20-binding inhibitor of NF-κB activation,).A20/TNFAIP3is involved in cell activation, regulation of cytokine signals, andapoptosis. Several research show that SNP rs2230926of this gene is associated with SLE inHan Chinese patients and down-regulation of this gene occurs in peripheral bloodmononuclear cells of patients with SLE. ABIN1/TNIP1interacts with A20/TNFAIP3and isexpressed in various tissues, including lymphocytes, spleen, and skeletal muscle, all ofwhich play roles in cell differentiation, apoptosis, and regulation of inflammatory responses.Gateva et al. identified ABIN1/TNIP1as one of five loci associated with risk for SLE inEuropean patients. The rs7708392locus of this gene is associated with SLE in European,Japanese, and Chinese Han populations. Thus, A20/TNFAIP3and ABIN1/TNIP1appear tobe important in the regulation of auto-immune responses in diverse populations of SLEpatients.Several recent animal studies have also examined the roles of these genes inautoimmune responses. For example, H evelmeyer et al.developed a new mouse strain withtissue-specific deletion of A20. Their experiments indicated that B-cell-specific deletion of A20reduced the number of marginal zone B-cells and that A20-deficient B-cells hadenhanced proliferation upon activation. These new mice also had higher levels of serumimmunoglobulins and up-regulation of autoantibodies. These results suggest aB-cell-specific role of A20in the development of autoimmunity due to a dysfunctionalinteraction of B-cells and T-cells. In addition, Chu et al. reported that selective loss of A20in the B-cells of aged mice caused inflammation and autoimmune responses, with elevationof IL-6, plasma cell expansion, and formation of autoantibodies. These results indicate thatdown-regulation of A20increased B-cell hyper-reactivity and suggest that this mechanismmay underlie the association of heritable human mutations or polymorphisms in A20withcertain autoimmune diseases.In the present study, we further analyzed the significance of these two genes in SLE bystudying a Han Chinese population in Southwestern China and comparison of patients whohad definite clinical diagnoses of SLE with age and gender-matched healthy controls. Inparticular, we studied polymorphisms of TNIP1and TNFAIP3in341SLE patients and356healthy controls and compared the expression of these genes in the peripheral bloodlymphocytes of patients and controls.Main results:1. SNP of TNIP1including rs7708392(C), rs6889239(C), rs4958437(C) andrs13168551(C) were risk loci of SLE (OR were1.429,1.417,1.299and1.454respectively，adjusted p<0.05)； rs10036748(C), rs960709(A) from TNIP1and rs719150(C) fromTNFAIP3were associated with low risk of SLE (OR were0.622,0.698and0.341respectively，adjusted p <0.05).2. SNP loci rs10036748with CC genotype and rs13168551with TT genotype wereassociated with low risk of SLE (OR were0.387and0.345respectively，adjusted p <0.05),rs719150from TNFAIP3with G allel(AG+GG) had higher risk of SLE compared with AAgenotype (OR was3.049，adjusted p <0.0001).3. Two TNIP1gene haplotypes (ATTGCGC and GTCCTAT) were associated with SLE(OR were0.695and0.649, p=0.0024and p=0.0246, respectively).4. Patients with SLE had significantly reduced expression of TNIP1/ABIN1relative tohealthy controls. 4. Expression of TNFAIP3/A20significantly increased in SLE patients compared tohealthy controls, and the expression level was associated with disease activity. SLE patientswith severe or moderate activity had significantly increased expression relative to patientswithout activity or with mild activity.5. We didn’t find any association between the7SNP loci (including rs4958437、rs13168551, rs960709, rs10036748, rs6889239, rs7708392from TNIP1and rs719150fromTNFAIP3)and expression of TNIP1/TNFAIP3or activity of SLE.In summary, analysis of SNPs in the TNIP1and TNFAIP3genes and expression ofthese genes in peripheral blood lymphocytes indicated these SNPs were associated with theoccurrence of SLE in Han Chinese patients. Future studies should examine the roles ofthese SNPs in the pathogenesis of SLE.