Genomics And Related Autoantibodies Of Idiopathic Inflammatory Myopathy In Chinese Han Population

Objective:Idiopathic inflammatory myopathies(?M)are a group of heterogeneous autoimmune diseases,characterized by different degrees of muscle inflammation.The etiology of ?M is still unknown.It is recognized that ?M are probably caused by the interaction between environmental factors and genetic factors.This study focused on the genetic characteristics of ?M in Han Chinese.Methods:(1)Candidate gene association studies were performed to analyze the association of susceptibility loci in other autoimmune diseases with ?M between 1017 patients with polymyositis(PM)/dermatomyositis(DM)and 1280 healthy controls of Han Chinese.(2)A genome-wide association study(GWAS)was conducted in 645 ?M and 1588 controls of Han Chinese.(3)Whole-exome sequencing(WES)was carried out in 60 patients with ?M and 20 healthy controls of Han Chinese.The results of WES were validated in 318 patients with ?M and 241 healthy controls using Sanger sequencing.Results:(1)The results of candidate gene association studies showed that the frequency of TNFSF4 rs844648 AG genotype was significantly higher in PM/DM than that in healthy control.TNFSF4 rs844648-A was associated with DM and PM/DM in the dominant model.The frequency of ANKRD55 rs7731626-G was significantly higher in DM and PM/DM than that in healthy control.The frequency of ANKRD55 rs7731626 GG genotype in PM/DM was significantly higher than that in healthy control.ANKRD55 rs7731626-A was associated with DM and PM/DM in both additive and dominant models.The frequency of GLIS3 rs7020673-G and rs10758593-A in PM was significantly higher than that in healthy controls.GLIS3 rs7020673-G and rs10758593-A were related to PM in both additive and dominant models.There is no significant difference in the frequencies of alleles and genotypes of rs280519,rs17000730 and rs280501 in TYK2 between PM,DM,PM/DM and healthy controls.(2)The results of GWAS revealed that rs35953215 and rs7770370 were significant associated with ?M of Han Chinese at a genome-wide level(P<5 × 10-8).(3)The results of WES showed that a rare variant in DDX58 was found in DM.In addition,rare variants in MUC5B and RINT1 were found in DM with cancer,and a rare variant in WDFY4 was found in juvenile dermatomyositis(JDM).Conclusion:In Han Chinese,?M shared susceptibility genes with other autoimmune diseases.Rs35953215 and rs7770370 were found to be significantly associated with IIM susceptibility at a genome-wide level for the first time.These two loci have not been reported in Caucasian and Japanese ?M GWAS.It is indicated that rs35953215 and rs7770370 are Han Chinese ?M specific loci.Variants in DDX58,MUC5B,RINT1 and WDFY4 are potential factors that may cause IIM.It is speculated that these gene mutations have a greater impact on gene function.The finding in this study play an important role in understanding the genetic characteristics of IIM and further exploring the pathogenesis of?M.Objective:Autoantibodies are of great significance for idiopathic inflammatory myopathies(?M).Myositis-specific autoantibodies(MSAs)and myositis-associated autoantibodies(MAAs)are important biomarkers for IIM.This study evaluated the clinical values of known myositis autoantibodies for ?M,and identified novel myositis autoantibodies using human proteome array.Methods:(1)Sera/plasma from 252 patients with IIM,100 patients with other autoimmune disease and 120 healthy controls were detected for MSAs and MAAs using line immunoassay(LIA)and enzyme-linked immunosorbent assay(ELISA).(2)The agreement of detecting anti-melanoma differentiation-associated gene 5(MDA5)and anti-transcription intermediary factor 1?(TIF1?)autoantibodies between LIA and ELISA was analyzed using Kappa statistics.(3)Novel autoantibodies were identified in IIM in a Chinese Han population using human proteome array containing 2148 proteins.The experiment was conducted in two phases.Phase ? included 40 ?M,30 other autoimmune disease and 20 healthy controls.Phase ? included 397 ?M,197 disease controls and 98 healthy controls.The novel IIM autoantibodies identified in a Chinese Han population were further validated in 176 IIM,43 disease controls and 26 healthy controls in an American Caucasian population.Results:(1)The LIA and ELISA results showed that the prevalences of anti-MDA5 and anti-Ro52 autoantibodies in polymyositis(PM)/dermatomyositis(DM)with interstitial lung disease(ILD)were significantly higher than those in the PM/DM without ILD;the prevalences of anti-TIF1? and anti-nuclear matrix protein 2(NXP2)autoantibodies in PM/DM with ILD was significantly lower than those in PM/DM without ILD;patients with anti-Mi-2 autoantibody had higher risk of developing muscle tenderness and lower risk of developing ILD than patients without anti-Mi-2 autoantibody;patients with anti-MDA5 autoantibody had higher risk of developing skin ulceration,ILD,and fever and lower risk of developing gastroesophageal reflux than patients without anti-MDA5 autoantibody;patients with anti-TIFly autoantibody had higher risk of developing periungual erythema and malignance,and had lower risk of developing arthralgia,ILD and fever than patients without anti-TIF1? autoantibody;patients with anti-aminoacyl-transfer RNA synthetase(ARS)autoantibody had higher risk of developing mechanic hands and gastroesophageal reflux than patients without anti-ARS autoantibody.(2)A moderate agreement was found between LIA and ELISA for anti-MDA5 and anti-TIF1?autoantibodies.(3)Anti-glvcine-N-methvltransferase(GNMT)autoantibodv were identified as a novel ?M-associated autoantibody in both Chinese Han population and American Caucasian population.Conclusions:MS As and MAAs had important clinical values for IIM.MS As were associated with specific clinical features.There was difference in detecting anti-MDA5 and anti-TIF1? autoantibodies using LI A and ELISA.Anti-GNMT autoantibody was identified as a novel ?M-associated autoantibodies with potential values for clinical application.