| Objective:IgG4-related disease(IgG4-RD)is a newly defined autoimmune disease of inflammatory fibrosis mediated by the immune system in recent years,which can affect various parts of the body.The pathogenesis of IgG4-RD is still unclear.As an autoimmune disease with complex etiology,like other autoimmune diseases,its genetic factors may be one of the important causes of IgG4-RD.Based on the genetic background of the Chinese Han,this study conducted the first genome-wide association studies(GWAS)study of IgG4-RD in China,aiming to explore the genetic susceptibility loci associated with IgG4-RD in the Chinese Han population.Methods:DNA samples from 1,161 IgG4-RD patients and 10,539 healthy controls were included in this study for GWAS chip detection.After data quality control,the microarray data of 1,115 IgG4-RD patients and 10,154 healthy controls were included in subsequent analysis.And based on the Han-MHC reference data set of the Chinese Han population,the IgG4-RD genotyping data was imputed with human leukocyte antigen(HLA)locus in the major histocompatibility complex region,and stepwise conditional analysis was performed to discover independent HLA susceptibility locus.In addition,this study evaluated the association between genetic variants and clinical characteristics of IgG4-RD patients.Results:66 single nucleotide polymorphisms(SNP)reached the genome-wide significance level(P<5E-08).Among them,a total of 54 SNPs located in the HLA region of chromosome 6 reached the genome-wide significance level.Twelve non-chromosome 6 SNPs reached genome-wide significance and were in nine genes(FCGR2B/FCRLA,CD46,CYP4A22,IGSF21,ABCA4/GCLM,STABI/KCNH8,ADCY8,TPTE2,GABRA5).Among them,rs 1340976 located between FCGR2B/FCRLA genes had the highest significance(P=4.10E-19,OR=1.65).After HLA imputation,6 HLA alleles,2 amino acid mutations and 1 SNP were confirmed to be independent signals with genome-wide significance for IgG4-RD.Conclusions:This study identified multiple IgG4-RD susceptibility loci,most of which were reported for the first time.Novel genetic variants associated with IgG4-RD were identified,and these findings further advance the understanding of the pathogenesis of IgG4RD from a genomic perspective.This study provides new directions for future research and patient treatment.Objective:The pathogenesis of IgG4-related disease(IgG4-RD)remains unclear.The clinical manifestations of IgG4-RD are often similar other diseases,including pancreatic cancer(PC)and Sj?gren’s syndrome(SS),which may lead to misdiagnosis.The treatment options and clinical prognosis of these diseases vary greatly,and it is of great value to differentiate these easily confused diseases.This study aims to explore the metabolic changes of IgG4-RD,PC,and SS,and to discover potential metabolic biomarkers for differential diagnosis.Methods:A non-targeted liquid chromatography-tandem mass spectrometry metabolomics analysis was performed on a cohort consisting of healthy controls(HC,n=30)and patients with newly diagnosed IgG4-RD(n=87),pancreatic cancer(PC,n=33),and Sjogren’s syndrome(SS,n=3 1).The raw data were split into training and testing sets in a 7:3 ratio.After total sum normalization and pareto-scaling preprocessing,multidimensional statistical analyses,including unsupervised principal component analysis and orthogonal partial least squares discriminant analysis,were only performed on the training set.The random forest machine learning model was used to determine the value of metabolites in differential diagnosis and the prediction of disease prognosis,and validating the model by using testing set.One thousand trees were constructed and repeated 100 times.The out-ofbag sample classification accuracy was determined for each tree under both random permutation and non-permutation of variable values.and the prediction accuracy after permutation was subtracted from the prediction accuracy before permutation to obtain the importance scores of all trees in the forest.The importance scores were used to identify biomarkers and remove non-informative variables.Results:Numerous differentially expressed metabolites were found in multiple group comparisons.The ATP-binding cassette transporter pathway was significantly upregulated in the IgG4-RD group compared to other control groups.Five metabolites were identified as valuable biomarkers for IgG4-RD.The combination of caffeic acid and maltotetraose showed high diagnostic value in distinguishing IgG4-RD from HC,with an area under the curve(AUC)of 1.The combination of D-glutamic acid and 1-stearoyl-2-arachidonoyl-sn-glycero3-phosphoserine could fully differentiate IgG4-related pancreatitis from PC(AUC=1).Hydroxyproline was valuable in distinguishing IgG4-related sialadenitis or dacryoadenitis from SS(AUC=1).The combination of betaine.1-(1 Z-hexadecenyl)-sn-glycero-3phosphocholine,Pi40:8.uracil,and N1-methyl-2-pyridone-5-carboxamide showed moderate predictive ability(AUC=0.8)for predicting the risk of recurrence in IgG4-RD patients.Some metabolic biomarkers were found to be associated with clinical features of IgG4-RD.The level of caffeic acid was positively correlated with serum IgG,IgG1,and IgG4 levels in IgG4RD patients,while hydroxyproline was found to be negatively correlated with ESR in IgG4RD patients.Conclusion:This study revealed the metabolic changes in IgG4-RD and provided new insights for a deeper understanding of the disease.Different metabolic patterns were observed in IgG4-RD patients.Valuable metabolic biomarkers were identified that can be used for the diagnosis of IgG4-RD and to distinguish it from PC and SS,and can also be used for the prognosis of IgG4-RD.Objective:IgG4-related disease(IgG4-RD)is an immune-mediated fibroinflammatory disease with heterogeneous manifestations,characterized by subacute masses or diffuse organ swelling and extensive fibrosis of affected tissues,often accompanied by elevated serum IgG4 levels.Human epididymis protein-4(HE4)has been proposed as a biomarker reflecting the degree of fibrosis in various diseases and involved in fibrosis formation of fibrotic diseases.This study hypothesized that HE4 may play a role in the fibrosis of IgG4-RD and could be a potential biomarker for this disease,aiming to explore the utility of HE4 as a potential clinical biomarker for fibrosis in IgG4-RD.Methods:Plasma HE4 levels were measured by electrochemiluminescence immunoassay in 136 newly diagnosed IgG4-RD patients,94 IgG4-RD patients with stable disease after treatment,and 73 healthy individuals.Immunohistochemistry and Masson’s trichrome staining were used to compare HE4 expression levels and fibrosis extent in pancreatic tissues of 15 IgG4-RD patients and 10 disease controls.The correlation between HE4 levels and laboratory indices and organ functional impairment was evaluated,and the utility of HE4 as a biomarker for fibrosis and prognosis in IgG4-RD was assessed.Results:Plasma HE4 levels in IgG4-RD patients were significantly elevated compared to healthy controls.However,plasma HE4 levels remained stable during follow-up in treated IgG4-RD patients.The optimal HE4 cutoff value for identifying IgG4-RD patients was determined to be 50.8 pmol/L by receiver operating characteristic curve analysis,with an area under the curve of 0.791,Elevated HE4 levels in patient plasma were positively correlated with various laboratory indices and organ functional impairment and could predict potential organ damage in IgG4-RD patients.Additionally,immunohistochemistry results showed high expression of HE4 in affected organs of IgG4-RD patients,and HE4 levels were closely associated with fibrosis extent,suggesting that HE4 could be used to evaluate internal organ damage and fibrosis.Further analysis revealed that patients with high HE4 expression had a poorer prognosis,were more likely to receive glucocorticoid or immunosuppressive therapy,and had a higher risk of adverse outcomes during follow-up(HR=2.741)compared to those with low HE4 expression,even with stronger treatment regimens.Conclusion:The results of this study indicate that HE4 can serve as a biomarker for IgG4-RD,as it is associated with various baseline clinical features,internal organ damage,and fibrosis extent in affected organs,and can predict the prognosis of IgG4-RD patients. |
