Systemic lupus erythematosus (SLE) is a prime example of how the interplay between genetic and environmental factors can trigger systemic autoimmunity, particularly in young women. Although clinical disease can take years to manifest, risk is established by the unique genetic makeup of an individual. Genome-wide association studies have identified almost 200 SLE-associated risk loci, yet unravelling the functional effect of these loci remains a challenge. New analytic tools have enabled researchers to delve deeper, leveraging DNA sequencing and cell-specific and immune pathway analysis to elucidate the immunopathogenic mechanisms. Both common genetic variants and rare non-synonymous mutations can interact to increase SLE risk. Notably, variants strongly associated with SLE are often located in genome super-enhancers that regulate MHC class II gene expression. Additionally, the 3D conformations of DNA and RNA contribute to genome regulation and innate immune system activation. Improved therapies for SLE are urgently needed and current and future knowledge from genetic and genomic research should provide new tools to facilitate patient diagnosis, enhance the identification of therapeutic targets and optimize testing of agents.

系统性红斑狼疮 (SLE) 是遗传和环境因素之间的相互作用如何引发系统性自身免疫的一个典型例子，尤其是在年轻女性中。尽管临床疾病可能需要数年时间才能显现出来，但风险是由个体独特的基因组成决定的。全基因组关联研究已识别出近 200 个与 SLE 相关的风险位点，但阐明这些位点的功能效应仍然是一个挑战。新的分析工具使研究人员能够更深入地研究，利用 DNA 测序、细胞特异性和免疫通路分析来阐明免疫致病机制。常见的基因变异和罕见的非同义突变可以相互作用，增加系统性红斑狼疮的风险。值得注意的是，与 SLE 密切相关的变异通常位于调节 MHC II 类基因表达的基因组超级增强子中。此外，DNA 和 RNA 的 3D 构象有助于基因组调控和先天免疫系统激活。迫切需要改进系统性红斑狼疮的治疗方法，当前和未来的遗传和基因组研究知识应该提供新的工具来促进患者诊断、加强治疗靶点的识别和优化药物测试。