Genome-wide identification of RNA modification-related single nucleotide polymorphisms associated with rheumatoid arthritis.

RNA modification plays important roles in many biological processes, such as gene expression control. The aim of this study was to identify single nucleotide polymorphisms related to RNA modification (RNAm-SNPs) for rheumatoid arthritis (RA) as putative functional variants. We examined the association of RNAm-SNPs with RA in summary data from a genome-wide association study of 19,234 RA cases and 61,565 controls. We performed eQTL and pQTL analyses for the RNAm-SNPs to find associated gene expression and protein levels. Furthermore, we examined the associations of gene expression and circulating protein levels with RA using two-sample Mendelian randomization analysis methods. A total of 160 RNAm-SNPs related to m6A, m1A, A-to-I, m7G, m5C, m5U and m6Am modifications were identified to be significantly associated with RA. These RNAm-SNPs were located in 62 protein-coding genes, which were significantly enriched in immune-related pathways. RNAm-SNPs in important RA susceptibility genes, such as PADI2, SPRED2, PLCL2, HLA-A, HLA-B, HLA-DRB1, HLA-DPB1, TRAF1 and TXNDC11, were identified. Most of these RNAm-SNPs showed eQTL effects, and the expression levels of 26 of the modifiable genes (e.g., PADI2, TRAF1, HLA-A, HLA-DRB1, HLA-DPB1 and HLA-B) in blood cells were associated with RA. Circulating protein levels, such as CFB, GZMA, HLA-DQA2, IL21, LRPAP1 and TFF3, were affected by RNAm-SNPs and were associated with RA. The present study identified RNAm-SNPs in the reported RA susceptibility genes and suggested that RNAm-SNPs may affect RA risk by affecting the expression levels of corresponding genes and proteins.

Wang M ，Wu J ，Lei S ，Mo X ... -  《BMC GENOMICS》

Genome-Wide Identification of Cell Type-Specific Susceptibility Genes for SLE Through the Analysis of RNA Modification-Associated SNPs.

Zhang H ，Fan K ，Chen Y ，Xu P ，Zhang Z ，Mo X ，Guo Y ... -  《-》

Genome-Wide Identification of RNA Modifications for Spontaneous Coronary Aortic Dissection.

RNA modification plays important roles in many biological processes such as gene expression control. Genetic variants that affect RNA modification may have functional roles in aortic dissection. The aim of this study was to identify RNA modifications related to spontaneous coronary artery dissection (SCAD). We examined the association of RNA modification-associated single-nucleotide polymorphisms (RNAm-SNPs) with SCAD in summary data from a genome-wide association study (GWAS) of European descent (270 SCAD cases and 5,263 controls). Furthermore, we performed expression quantitative loci (eQTL) and protein quantitative loci (pQTL) analyses for the RNAm-SNPs using publicly available data. Functional enrichment and protein-protein interaction analyses were performed for the identified proteins. We found 11,464 unique RNAm-SNPs in the SCAD GWAS dataset, and 519 were nominally associated with SCAD. Nine RNAm-SNPs were associated with SCAD at p < 0.001, and among them, seven were N6-methyladenosine (m6A) methylation-related SNPs, one (rs113664950 in HLA-DQB1) was m7G-associated SNP, and one [rs580060 in the 3'-UTR of Mitochondrial Ribosomal Protein S21 (MRPS21)] was A-to-I modification SNP. The genome-wide significant SNP rs3818978 (SCAD association p = 5.74 × 10-10) in the 5'-UTR of MRPS21 was related to m6A modification. These nine SNPs all showed eQTL effects, and six of them were associated with circulating protein or metabolite levels. The related protein-coding genes were enriched in specific Gene Ontology (GO) terms such as extracellular space, extracellular region, defense response, lymphocyte migration, receptor binding and cytokine receptor binding, and so on. The present study found the associations between RNAm-SNPs and SCAD. The findings suggested that RNA modification may play functional roles in SCAD.

Chai T ，Tian M ，Yang X ，Qiu Z ，Lin X ，Chen L ... -  《Frontiers in Genetics》

TRAF1 polymorphisms associated with rheumatoid arthritis susceptibility in Asians and in Caucasians.

Han TU ，Bang SY ，Kang C ，Bae SC ... -  《ARTHRITIS AND RHEUMATISM》

Coronary artery disease risk factors affected by RNA modification-related genetic variants.

Single nucleotide polymorphisms that affect RNA modification (RNAm-SNPs) may have functional roles in coronary artery disease (CAD). The aim of this study was to identify RNAm-SNPs in CAD susceptibility loci and highlight potential risk factors. CAD-associated RNAm-SNPs were identified in the CARDIoGRAMplusC4D and UK Biobank genome-wide association studies. Gene expression and circulating protein levels affected by the RNAm-SNPs were identified by QTL analyses. Cell experiments and Mendelian randomization (MR) methods were applied to test whether the gene expression levels were associated with CAD. We identified 81 RNAm-SNPs that were associated with CAD or acute myocardial infarction (AMI), including m6A-, m1A-, m5C-, A-to-I- and m7G-related SNPs. The m6A-SNPs rs3739998 in JCAD, rs148172130 in RPL14 and rs12190287 in TCF21 and the m7G-SNP rs186643756 in PVT1 were genome-wide significant. The RNAm-SNPs were associated with gene expression (e.g., MRAS, DHX36, TCF21, JCAD and SH2B3), and the expression levels were associated with CAD. Differential m6A methylation and differential expression in FTO-overexpressing human aorta smooth muscle cells and peripheral blood mononuclear cells of CAD patients and controls were detected. The RNAm-SNPs were associated with circulating levels of proteins with specific biological functions, such as blood coagulation, and the proteins (e.g., cardiotrophin-1) were confirmed to be associated with CAD and AMI in MR analyses. The present study identified RNAm-SNPs in CAD susceptibility genes, gene expression and circulating proteins as risk factors for CAD and suggested that RNA modification may play a role in the pathogenesis of CAD.

Li R ，Zhang H ，Tang F ，Duan C ，Liu D ，Wu N ，Zhang Y ，Wang L ，Mo X ... -  《Frontiers in Cardiovascular Medicine》