Association Study Of IRF7, STAT4 And Systemic Lupus Erythematosus

Systemic lupus erythematosus(SLE) is a prototypic autoimmune disease characterized by presence of circulating autoantibodies against nuclear antigens.Several studies have demonstrated that the interferon(IFN) level in serum of SLE patients was raised,and was correlated with both disease activity and severity;patients with no autoimmune disease were found to induce autoantibodies or occasionally clinical SLE symptoms after the treatment of IFN;patients with SLE revealed to have typical 'IFN signature'.So,IFN has been identified as the central cytokine in the pathogenesis of SLE,and the abnormal activation of IFN signal pathway may also be identified as a main molecular phenotype in SLE patients.Interferon regulatory factor(IRF) is a kind of multifunctional transcriptional factor which can regulate the expression of IFN gene,and IRF7 is known as the master regulator in immune response dependent on typeâ… IFN because it can regulate all the process of IFN response.Although the etiology of SLE is unknown,the genetic susceptibility and the environmental factors may play the critical roles in it.Nowadays,more and more work is focused on the association between the genetic variations and SLE.Among them,IRF5 and signal transducer and activator of transcription 4(STAT4) are extensively researched.But SLE is a kind of disease which shows heterogeneity.So some susceptibility genes identified in a part of population remain to be checked in other cohorts.In this study,the associations of systemic lupus erythematosus in Chinese Han and the gene of IRF7 and STAT4 are to be explored.The real-time quantitative PCR technique was used to test the IRF7 mRNA expression levels in peripheral blood of patients and normal individuals.And then the levels were compared with the IFN level in serum,IFN score and SLEDAI score.The resequencing technique was used to screen out the single nucleotide polymorphisms(SNP) with a certain frequency in IRF7 and to accomplish the case-control research based on a large number of samples.The pyrosequencing technique was used to genotype the 3 STAT4 SNPs of patients and normal individuals,and then the statistics analysis was carried out.It is demonstrated that the expression level of IRF7 mRNA in SLE patients is significantly increased(P=0.0118),and is positively correlated with the IFN level in serum,IFN score and SLEDAI score which shows the activity and severity of disease(P values are 0.0044,0.0004 and 0.0105 respectively). Although 3 SNPs(rs10902179,rs34469296 and rs1061501) are found to have the frequency more than 5%in IRF7 gene,they all show no difference between the SLE patients and normal individuals.And even though 2 of the 3 SNPs (rs34469296 and rs10902179) can form a haplotype,it shows no relationship with the disease,either.About the gene of STAT4,the 3 SNPs tested here are significantly associated with the disease[rs11889341:P=0.01202,OR(95% CI)=1.22(1.044-1.424);rs7574865:P=0.003454,0R(95%CI)=1.25(1.076-1.451); rs8179673:P=0.004275,OR(95%CI)=1.274(1.079-1.505)],and the haplotpye composed of them show the significant difference between the patients and normal individuals as well.So it is concluded that although the increase of IRF7 expression may excessively activate the IFN pathway and lead to SLE,the evidence of relationship of disease on genetics remains insufficiency.So it is still too early to define IRF7 as a susceptibility gene of SLE.However,rs11889341, rs7574865 and rs8179673 of STAT4 are all associated with the pathogenesis of Chinese Han SLE,and it is clear that the STAT4 gene is a susceptibility gene of SLE among quite a few racial cohorts.