Genome-wide identification of cell type-specific susceptibility genes for Juvenile dermatomyositis through the analysis of N6-methyladenosine-associated SNPs.

IF 3.3 4区 医学 Q3 IMMUNOLOGY
Autoimmunity Pub Date : 2024-12-01 Epub Date: 2024-10-24 DOI:10.1080/08916934.2024.2419117
Huan Zhang, Kedi Fan, Zhentao Zhang, Yufan Guo, Xingbo Mo
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引用次数: 0

Abstract

Genome-wide association studies (GWASs) have pinpointed genetic loci associated with juvenile dermatomyositis (JDM). Functional genes within the GWAS loci may be cell type-specific, but their identity remains largely unknown. N6-methyladenosine (m6A) plays a pivotal role in regulating various cellular processes and is linked to autoimmune diseases. This study aimed to underscore the potential functional genes within the GWAS loci through the analysis of m6A-associated SNPs (m6A-SNPs), specifically within relevant cell types. JDM-associated m6A-SNPs were identified from the GWAS summary dataset. The correlation between m6A-SNPs and gene expression was assessed through bulk tissue and single-cell eQTL analyses. To further investigate the relationship between gene expression and JDM, Mendelian randomization analysis was employed. Additionally, differential expression analyses were conducted on bulk tissues, as well as single-cell transcriptomic data comprising 6 JDM patients and 11 juvenile controls (99,396 cells). Seven m6A-SNPs associated with JDM were identified. Bulk tissue analysis revealed differential expression of HLA-DPA1, HLA-DPB1, MICB, HLA-A, HLA-F, HLA-DQB2, HLA-DRB5, TAP2, PSMB9, MICA, AIF1, and DDX39B influenced by m6A-SNPs, all showing associations with JDM in both differential expression and Mendelian randomization analyses. In single-cell analysis, the six m6A-SNPs within the HLA locus acted as cell-type-specific eQTLs, correlating with the expression of HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQA1, HLA-DQB1 and HLA-DRB1 in myeloid, T or B cells. Notably, these genes displayed abnormal expression in T, B, and myeloid cells of JDM patients. The present study identified m6A-SNPs within JDM susceptibility genes, shedding light on the intricate interplay between m6A-SNPs, gene expression, and JDM.

通过分析与 N6-甲基腺苷相关的 SNPs,在全基因组范围内鉴定细胞类型特异性的幼年皮肌炎易感基因。
全基因组关联研究(GWAS)确定了与幼年皮肌炎(JDM)相关的基因位点。GWAS 基因位点中的功能基因可能具有细胞类型特异性,但它们的身份仍然不为人知。N6-甲基腺苷(m6A)在调节各种细胞过程中起着关键作用,并与自身免疫性疾病有关。本研究旨在通过分析与 m6A 相关的 SNPs(m6A-SNPs),特别是相关细胞类型中的 SNPs,来强调 GWAS 位点中的潜在功能基因。JDM 相关 m6A-SNPs 是在 GWAS 摘要数据集中发现的。通过大量组织和单细胞 eQTL 分析评估了 m6A-SNPs 与基因表达之间的相关性。为了进一步研究基因表达与 JDM 之间的关系,采用了孟德尔随机分析法。此外,还对大块组织以及由 6 名 JDM 患者和 11 名青少年对照(99,396 个细胞)组成的单细胞转录组数据进行了差异表达分析。结果发现了 7 个与 JDM 相关的 m6A-SNP。大量组织分析显示,HLA-DPA1、HLA-DPB1、MICB、HLA-A、HLA-F、HLA-DQB2、HLA-DRB5、TAP2、PSMB9、MICA、AIF1 和 DDX39B 的差异表达受到 m6A-SNPs 的影响,在差异表达和孟德尔随机化分析中均显示与 JDM 相关。在单细胞分析中,HLA 基因座上的六个 m6A-SNPs 起到了细胞类型特异性 eQTL 的作用,与骨髓细胞、T 细胞或 B 细胞中 HLA-A、HLA-B、HLA-C、HLA-DPB1、HLA-DQA1、HLA-DQB1 和 HLA-DRB1 的表达相关。值得注意的是,这些基因在 JDM 患者的 T、B 和髓系细胞中都显示出异常表达。本研究发现了 JDM 易感基因中的 m6A-SNP,揭示了 m6A-SNP、基因表达和 JDM 之间错综复杂的相互作用。
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来源期刊
Autoimmunity
Autoimmunity 医学-免疫学
CiteScore
5.70
自引率
8.60%
发文量
59
审稿时长
6-12 weeks
期刊介绍: Autoimmunity is an international, peer reviewed journal that publishes articles on cell and molecular immunology, immunogenetics, molecular biology and autoimmunity. Current understanding of immunity and autoimmunity is being furthered by the progress in new molecular sciences that has recently been little short of spectacular. In addition to the basic elements and mechanisms of the immune system, Autoimmunity is interested in the cellular and molecular processes associated with systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome, type I diabetes, multiple sclerosis and other systemic and organ-specific autoimmune disorders. The journal reflects the immunology areas where scientific progress is most rapid. It is a valuable tool to basic and translational researchers in cell biology, genetics and molecular biology of immunity and autoimmunity.
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