Study Of The Association Between IL-18 And Systemic Lupus Erythematosus

BackgroundSystemic lupus erythematosus（SLE）is a multi-system involved systemic autoimmune disease,and its pathogenesis is complex.The disease has a variety of phenotypes and clinical manifestations,ranging from mild cutaneous mucosal manifestations to multi-organ and severe central nervous system involvement.The main characteristics of the disease are overactivation of the immune system,increased autoantibodies and immune complexes due to cytokine release,complement activation and autoantibodies,and organ dysfunction.It has been reported that the prevalence and incidence of systemic lupus erythematosus vary,and the differences are mainly attributed to population differences,mainly affecting women of reproductive age,with a male to female ratio of 9 to 1.Some genetic,immune,endocrine and environmental factors play an important role in the pathogenesis of systemic lupus erythematosus.Interleukin-18（IL-18）is a cytokine that plays an important role in chronic inflammation and autoimmune diseases.Interleukin-18（IL-18）is a cytokine that plays an important role in chronic inflammation and autoimmune diseases.IL-18 is believed to be a cytokine with pro-inflammatory effects,inducing interferon-?（IFN-?）in peripheral blood mononuclear cells（PBMCs）as well as inflammatory and cytotoxic immune cell activity,leading to autoimmunity.Active IL-18 binds to IL-18Rα,which results in recruitment of IL-18Rβinto the signaling complex.IL-18Rβthen recruits My D88 to trigger the NF-KB signaling cascade,which leads to IFN-?production.IL-18 is involved in the activation of helper T cells Th1 and natural killer cells（NK）,but is also involved in the activation of Th2producing,T cells and macrophages.IL-18 may have a potential relationship with common autoimmune diseases.Currently,a large number of observational studies have investigated circulating IL-18 levels in patients with autoimmune diseases,and the circulating IL-18 levels are significantly higher in patients with systemic lupus erythematosus（SLE）compared to the control group.ObjectiveThis study aimed to explore the association between circulating IL-18 levels and the onset of SLE through a meta-analysis.The causal relationship between the circulating IL-18 levels and the risk of developing SLE was explored by the TSMR analysis.We further verified the association between the SNP locus highly associated with IL-18 and the onset of SLE in Anhui Han population.MethodsThe combined effect of IL-18 on SLE patients was assessed by a meta-analysis with a standardized Mean Difference（SMD）and its 95%confidence interval（CI）.Significant Single-Nucleotide polymorphism（Single Nucleotide Polymorphisms,snps）associated with serum peripheral blood circulating IL-18 levels(P<5×10^-8)were collected from a genome-wide association studies（GWAS）study involving 30 931participants of European ancestry as Instrumental variants（IV）.These snps will be reviewed in a separate SLE GWAS study that included 23 210 participants of European ancestry.Two-sample Gregor Mendel randomization（TSMR）analysis including MR-egger,Inverse variance weighted（IVW）,and weighted median method was used to estimate the causality of IL-18 levels in peripheral blood circulation in SLE.A self-made questionnaire was used to collect the general demographic information and clinical data of SLE patients.Data of SLE patients were collected from two hospitals in Anhui province,and an independent Anhui verification population was established,including 372 cases in the case group and 1809 cases in the control group.We used PLINK1.07 to conduct an association analysis based on the additive model in the Anhui validated population to compare the relationship between the studied peripheral blood circulation IL-18 and SLE susceptibility.ResultsWe searched Pub Med,Web of Science,and Embase online databases for all available articles on IL-18 and SLE prior to December 2022.A total of 775 articles were initially retrieved.After reading the title and abstract,we excluded duplicate articles and studies that did not meet the above inclusion criteria,excluded 767articles,and ended up retaining eight separate studies involving 834 participants of European descent.Meta-analysis results showed that in eight independent studies including 864 participants,peripheral blood circulating IL-18 concentrations were higher in SLE patients compared with healthy controls[SMD=0.974,（95%CI0.822,1.126）,P<0.001].We extracted six SNPs from pooled data on IL-18 in European populations,in which none of the alleles of the variable were located in the HLA region.After calculation,the F statistic of these SNPs is greater than 10,and there is no LD relationship between them.These evidences show that the selected IVs are stable and can ensure the reliability of MR Results.Median weighting,mode weighting,inverse variance weighting,MR-Egger regression and MR-PRESSO method were used to evaluate the strength of the causal association between TL and SLE risk.Two-sample Mendelian randomization showed that the results of IVW method[OR=1.32,（95%CI1.15,1.50）,P<0.001]indicated a causal relationship between peripheral blood circulation IL-18 level and SLE,and was consistent with weighted median method[OR=1.30,（95%CI 1.04,1.63）,P<0.001],both of which indicated a causal relationship between peripheral blood circulation IL-18 level and SLE.The result of MR-Egger regression test[OR=1.10,（95%CI 0.50,2.40）,P=0.725]could not find a causal relationship between serum IL-18 concentration and SLE risk.In addition,heterogeneity test results showed that our current MR Analysis found no evidence of heterogeneity among SNPS selected by MR-Egger regression（P=0.794）and IVW（P=0.793）methods.The results of pleiotropy analysis showed that the pleiotropy among the extracted SNPS had no effect on the analysis results（P=0.477）.To explore whether the conclusions reached in Europeans also apply to Asians,we first conducted a meta-analysis to investigate the genetic association of the IL-18gene region with SLE risk in Asian and cross-ethnic populations,and conducted a replicated TSMR study searching for these loci in Anhui SLE GWAS data.The results of the study on the relationship between IL-18 and SLE susceptibility in Anhui Han population showed that SNP rs5744249 was significantly correlated in Anhui Han population（P<0.05）,indicating that SNP rs5744249 significantly increased the risk of SLE in Anhui Han population.ConclusionsThe meta-analysis results showed that the IL-18 levels in the peripheral blood circulation were higher in SLE patients,while the IL-18 level was lower in the healthy control population.The results of TSMR analysis indicated that increased IL-18 levels in peripheral blood circulation and increased risk of SLE compared with healthy control population.The results of IL-18 gene polymorphism（SNP）and SLE susceptibility in Anhui Han population showed that SNP rs5002812 associated with IL-18 and the susceptibility to SLE pathogenesis in Anhui Han population.