Decoding the genetic landscape of juvenile dermatomyositis: insights from phosphorylation-associated single nucleotide polymorphisms.

Genome-wide association studies (GWASs) have identified genetic susceptibility loci associated with juvenile dermatomyositis (JDM). Single nucleotide polymorphisms related to phosphorylation (phosSNPs) are critical nonsynonymous mutations exerting substantial influence on gene expression regulation. The aim of this study was to identify JDM susceptibility genes in the GWAS loci by the use of phosSNPs. We explored quantitative trait loci (QTLs) among the phosSNPs associated with JDM using data from eQTL (bulk tissues and single-cell) and pQTL studies. For gene expression and protein levels significantly influenced by JDM-associated phosSNPs, we assessed their associations with JDM through MR analyses. Additionally, we conducted differential expression gene analyses, incorporating single-cell transcriptomic profiling of 6 JDM cases and 11 juvenile controls (99,396 cells). We identified 31 phosSNPs situated in the 6p21 locus that were associated with JDM. Half of these phosSNPs showed effects on gene expression in various cells and circulating protein levels. In MR analyses, we established associations between the expression levels of pivotal JDM-associated genes, including MICB, C4A, HLA-DRB1, HLA-DRB5, and PSMB9, in skin, muscle, or blood cells and circulating levels of C4A, with JDM. Utilizing single-cell eQTL data, we identified a total of 276 association signals across 14 distinct immune cell types for 28 phosSNPs. Further insights were gained through single-cell differential expression analysis, revealing differential expression of PSMB9, HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQA1, HLA-DQB1, and HLA-DRB1 in immune cells. The present study pinpointed phosSNPs within susceptibility genes for JDM and unraveled the intricate relationships among these SNPs, gene expression levels, and JDM.

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

Genome-wide identification of cell type-specific susceptibility genes for Juvenile dermatomyositis through the analysis of N(6)-methyladenosine-associated SNPs.

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

Phosphorylation-related SNPs influence lipid levels and rheumatoid arthritis risk by altering gene expression and plasma protein levels.

Phosphorylation-related single-nucleotide polymorphisms (phosSNPs) are missense SNPs that may influence protein phosphorylation. The aim of this study was to evaluate the effect of phosSNPs on lipid levels and RA. We examined the association of phosSNPs with lipid levels and RA in large-scale genome-wide association studies (GWAS) and performed random sampling and fgwas analyses to determine whether the phosSNPs associated with lipid levels and RA were significantly enriched. Furthermore, we performed QTL analysis and Mendelian randomization analysis to obtain additional evidence to be associated with the identified phosSNPs and genes. We found 483 phosSNPs for lipid levels and 243 phosSNPs for RA in the GWAS loci (P < 1.0 × 10-5). SNPs associated with high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, Total cholesterol (TC) and RA were significantly enriched with phosSNPs. Almost all of the identified phosSNPs showed expression quantitative trait loci (eQTL) effects. A total of 48 protein QTLs and 9 metabolite QTLs were found. The phosSNP rs3184504 (p.Trp262Arg) at SH2B3 was significantly associated with RA, SH2B3 expression level, and plasma levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, TC, hypoxanthine and 80 proteins, including beta-2-microglobulin. SH2B3 was differentially expressed between RA cases and controls in peripheral blood mononuclear cells and synovial tissues. Mendelian randomization analysis showed that SH2B3 expression level was significantly associated with TC level and RA. Plasma beta-2-microglobulin level was causally associated with high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, TC levels and RA. The findings suggested that phosSNPs may play important roles in lipid metabolism and the pathological mechanisms of RA. PhosSNPs may influence lipid levels and RA risk by altering gene expression and plasma protein levels.

Mo X ，Guo Y ，Qian Q ，Fu M ，Zhang H ... -  《-》

HLA class II haplotype and autoantibody associations in children with juvenile dermatomyositis and juvenile dermatomyositis-scleroderma overlap.

Wedderburn LR ，McHugh NJ ，Chinoy H ，Cooper RG ，Salway F ，Ollier WE ，McCann LJ ，Varsani H ，Dunphy J ，North J ，Davidson JE ，Juvenile Dermatomyositis Research Group (JDRG) ... -  《-》

Deciphering cell-specific genetic insights: Unraveling the immunogenetic landscape of systemic lupus erythematosus.

Functional genes within genomic loci associated with systemic lupus erythematosus (SLE), as identified by genome-wide association studies, exhibit cell-specific characteristics. This study delves into the impact of genetic variants within SLE loci on gene expression in different types of immune cells, unraveling the complex interplay between genetics and immunopathogenesis. Through the integration of genetic association and single-cell transcriptomic sequencing data, we identified potential cell-specific susceptibility genes for SLE across diverse immune cell subsets. The single-cell eQTL analysis revealed 30,409 associations involving 3583 SLE-associated SNPs. These SNPs exhibited associations with expression levels of 147 genes across 14 distinct cell types. The single-cell summary data-based Mendelian randomization (SMR) analysis identified 119 significant associations between the expression levels of 44 genes and SLE. Notably, myeloid cells exhibited associations solely within the MHC region, while T, B, and natural killer cells showed associations with both MHC and non-MHC genes in relation to SLE. Analysis of single-cell transcriptomic data from 33 children SLE cases and 11 match controls (227,303 cells), as well as 7 adult SLE cases and 5 match controls (78,414 cells) highlights differential expression of key genes. Notably, genetic variants within HLA-DRB1, HLA-DRB5, HLA-DQA1, HLA-DQB1, IRF7, IRF5, BLK and HLA-DPA1 play a pivotal role in mediating immune dysregulation in specific immune cell types. Our study contributes to a comprehensive understanding of the intricate relationships between genetics, gene expression and SLE susceptibility. The findings shed light on the cell-specific impacts of genetic variants within SLE-associated genomic loci.

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