| Background:Rheumatoid arthritis(RA)is a chronic destructive autoimmune arthritis characterized by chronic inflammation of the synovium,especially in small joints,which often leads to the destruction of adjacent bones and articular cartilage,often accompanied by systemic manifestations such as osteoporosis,fatigue,anemia,and significantly reduces people’s quality of life.RA is caused by both genetic and environmental factors,and its heritability is about 60%.Identification of genetic variation is crucial to the pathological mechanism of RA.Genome wide association studies(GWAS)have identified over 100 RA related genomic regions,but the functional variations within them are still not fully understood.RNA modification plays an important role in the occurrence and development of diseases.RNA modification associated SNPs(RNAm SNPs)may be functional variants that affect RA risk.Objective:Identify RNA modifications related to RA and systematically explore the regulatory role of related sites in RA;Exploring the risk factors of new RA and providing new clues or targets for its prevention and treatment is of great significance for the prevention and treatment of RA.Methods:This study consists of three steps:Firstly,the association between RNAm SNP and RA was detected in a genome-wide association study of 19234 RA cases and 61565 controls.Based on the RMVar database,RNAm SNPs significantly correlated with RA were screened.Secondly,expression quantitative trait loci(eQTL)analysis was conducted to evaluate whether RNAm-SNP has a potential impact on gene expression;Simultaneously conducting differential expression analysis and summary data based Mendelian randomization(SMR)to test whether these gene expressions are associated with RA.Further research was conducted to obtain data for eQTL,differential expression analysis,and genetic risk score(GRS)validation of RA related genes.Finally,protein quantitative trait loci(pQTL)were used to investigate the association between RNAm-SNP and plasma proteins,and Mendelian randomization(MR)analysis was used to screen for RA related risk proteins.Results:A total of 160 RNAm-SNPs significantly related to RA were screened(P<5.0 × 10-8),including 135 m6A、9 A-to-I、9 m1A、1 m5C、1 m5U、6 m7G 和 1 m6Am related SNPs.Among these RNAm-SNPs,119 are located in 62 protein-coding genes,and 41 are located in lncRNAs or pseudogenes.These 62 protein-coding genes are significantly enriched in GO items of immune-related pathways and biological processes.Through eQTL analysis,it was found that 51 RNAm SNPs were correlated with the expression level of their respective genes in blood cells.Through SMR analysis,a significant correlation was detected between the expression levels of 26 genes and RA in blood cells(PSMR<5.0 × 10-6).Differential expression analysis found that the gene expression levels of important RA susceptibility genes such as HLA-DQB1,DAXX,HLA-A,HLA-C,HLA-DDPB1,HLA-DQA1,HLA-DQB1,PADI2,PHF19,RNASET2,and VARS2 in blood cells are related to RA.According to our data,there are also differences in the expression levels of HLA-A,HSPA1A,and MICB in PBMC between case control groups.In addition,the expression level of HLA-A in PBMC is related to RAGRS.Through pQTL analysis,602 pQTL signals were found(P<5.0×10-6),which contains 107 RNAm-SNPs and 82 proteins.MR analysis found a significant correlation between the levels of 9 proteins in plasma and RA.The validation study using RA GWAS data from 2021 also found a potential causal relationship between these 9 proteins and RA.The association between plasma CFB,HLA-DQA2,and LRPAP1 levels and RA was significant in all MR analyses.Conclusion:This study identified RNAm-SNPs in RA susceptibility genes and found that these RNAm-SNPs are associated with blood cell gene expression and plasma protein levels,and there is a potential causal relationship between these gene expression and plasma protein levels and RA.This suggests that RNAm-SNPs may affect RA risk by affecting the expression levels of corresponding genes and proteins. |
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