IRF7 Genetic Regulatory Mechanism Analysis In Systemic Lupus Erythematosus And A Retrospective Analysis Of Thrombosis In SLE

Background:Systemic lupus erythematosus(SLE)is a typical autoimmune diseases with production of several auto antibodies and deposition of immune complexes.The etiology and pathogenesis of SLE is not fully understood.Genetic factors and environmental factors should be taken into account of SLE initiation.Lupus nephritis(LN)is one of the most common clinical manifestations and the maj or cause of mortalitySNP rs1131665,located in the gene of Interferon gene regulation 7(IRF7),was found associated with SLE.The polymorphisms could change IRF7 protein activity causing downstream type ? interferons(Type ? interferon,?-IFN)pathway activation which may be involved in the occurrence of SLE.mRNA expression profiling data of LN and lupus animal model kidney showed increased expression level of IRF7 in lupus nephritis.Interaction between ?-IFN and residential cells in the kidney is still not comprehensivly understood.Glomerular endothelial cells is the firts cell type which could contact circulatory immune complexes.Further studying the interraction of IRF7 and glomerular endothelial cels would help to understand the pathogenesis of SLE.On the other hand,microvascular endothelial cell activation,which could lead to arterial and venous thrombosis,may play a key role in SLE systemic damages.To better monitor and prevention of thrombosis in SLE,we explored risk factors among SLE patients with thrombosis.Methods:We carried out fine mapping of IRF7 gene between SLE and controls.Then we tried to explore the possible pathogenic mechanisms of the risk SNPs function in vitro.We analysed the local IRF7 expression in LN kidney and related endothelial function in vitro.By retrospective case-control study of SLE with or without thrombosis,we explored the possible risk factors of SLE associated thrombosis.Results:rs1060502(K179E),located in the IRF7 gene coding region was found significantly associated with SLE(p=0.0057,ORF=1.735,95%CI 1.030-2.923).rs7022966,located in the 3 'untranslated region of IRF7 gene was found associated with various subtypes of SLE.rs702966 was significantly associated with LN(p<0.0001,OR=0.012,95%CI 0.008-0.018).K179E polymorphism caused amino acid change,which convert Lysine(K)to Glutamate(E).The polymorphism may change the state of pan lysine acetylation of lysine,which may further influence IFN-simulated response elements(ISRE)binding ability.rs702966 G risk allele may affect the expression of IRF7 mRNA levels which may involved in the pathogenic role in SLE.IRF7 was found upregulated in both mRNA and protein levels in LN kidney tissues.IRF7 glomerular expression index was found associated with SLEDAI(p=0.0443,r=0.2723),anti-dsDNA antibodies(p=0.0091,r=0.3581),LN activity score(p=0.0365,r=0.2827),C3(p=0.0339,r=-0.2892),C4(p=0.0335,r=-0.2955)and Ccr(p=0.0163,r=-0.3225).All those indicated that IRF7 level was correlated with the severity and activity of disease.IRF7 was found co-localized with glomerular endothelial cells.In vitro,we found that IRF7 could lead to endothelial cells overexpression of I-IFN inducible genes,chemokine genes and endothelial cell adhesion molecules genes,meanwhile IRF7 could also influence endothelial cell permeability and apoptosis.IRF7 expression in kidey may cause local inflammation and endothelial damage which may cause the occurence of LN.An elevated partial aPL score is a strong risk factor for thrombosis in SLE patients and is a useful tool to predict recurrent thrombosis.Partial aPL score and simplified aPL score,although comprising fewer items than the original aPL score,also represent valuable quantitative indices for APS diagnosis.Conclusion:IRF7 gene is a susceptibility gene of SLE among Chinese Han population.Polymorphism in IRF7 may affect IRF7 protein function or mRNA expression thus may cause downstream I-IFN activation.IRF7 was upregulated and its expression level was correlated with LN acitivity,SLE disease activity and renal function.IRF7 could activate glomerular endothelial cells to express ISGs and adhesion molecules,increase cell permeability and induce apoptosis.IRF7 may be a key facor in the pathogenesis of LN.Partial aPL score and simplified aPL socore can effectively predict the risk of thrombosis in SLE.