Department of Epidemiology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, China.
Department of Epidemiology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, China; Center for Genetic Epidemiology and Genomics, School of Public Health, Suzhou Medical College of Soochow University, China.
Mol Immunol. 2024 Nov;175:165-175. doi: 10.1016/j.molimm.2024.10.005. Epub 2024 Oct 30.
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.
基因组中与系统性红斑狼疮（SLE）相关的功能基因，通过全基因组关联研究确定，具有细胞特异性特征。本研究深入探讨了 SLE 基因座内的遗传变异对不同类型免疫细胞中基因表达的影响，揭示了遗传与免疫发病机制之间的复杂相互作用。通过遗传关联和单细胞转录组测序数据的整合，我们确定了 SLE 相关免疫细胞亚群中潜在的细胞特异性易感基因。单细胞 eQTL 分析揭示了 3583 个 SLE 相关 SNP 涉及 30409 个关联。这些 SNP 与 14 种不同细胞类型中 147 个基因的表达水平相关。基于单细胞汇总数据的孟德尔随机化（SMR）分析确定了 44 个基因表达水平与 SLE 之间的 119 个显著关联。值得注意的是，髓样细胞仅在 MHC 区域内表现出关联，而 T、B 和自然杀伤细胞与 MHC 和非 MHC 基因均与 SLE 相关。对 33 例儿童 SLE 病例和 11 例匹配对照（227303 个细胞）以及 7 例成人 SLE 病例和 5 例匹配对照（78414 个细胞）的单细胞转录组数据进行分析，突出了关键基因的差异表达。值得注意的是，HLA-DRB1、HLA-DRB5、HLA-DQA1、HLA-DQB1、IRF7、IRF5、BLK 和 HLA-DPA1 内的遗传变异在调节特定免疫细胞类型中的免疫失调方面发挥了关键作用。本研究有助于全面了解遗传、基因表达和 SLE 易感性之间的复杂关系。研究结果揭示了 SLE 相关基因组基因座内遗传变异的细胞特异性影响。
