Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of SLE variant accessibility and gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear antibodies characteristic of SLE. Of the ~400 potential regulatory variants identified, 90% exhibit spatial proximity to genes distant in the 1D genome sequence, including variants that loop to regulate the canonical TFH genes BCL6 and CXCR5 as confirmed by genome editing. SLE ‘variant-to-gene’ maps also implicate genes with no known role in TFH/SLE disease biology, including the kinases HIPK1 and MINK1. Targeting these kinases in TFH inhibits production of IL-21, a cytokine crucial for class-switched B cell antibodies. These studies offer mechanistic insight into the SLE-associated regulatory architecture of the human genome.

系统性红斑狼疮（SLE）由破坏多个组织的自身反应性抗体介导。全基因组关联研究（GWAS）将超过60个基因座与SLE风险联系起来，但因果变异和效应基因在很大程度上尚不清楚。我们在人类滤泡辅助性T细胞（TFH）中生成了SLE变体可及性和基因连通性的高分辨率空间图，该细胞是SLE的抗核抗体所需的细胞类型。在大约400种潜在的调控变异中，有90％的变异与一维基因组序列中远处的基因在空间上接近，包括循环调控经典TFH基因BCL6和CXCR5的变异经基因组编辑确认。SLE“变异至基因”图谱还暗示了在TFH / SLE疾病生物学中没有已知作用的基因，包括激酶HIPK1和MINK1。在TFH中靶向这些激酶可抑制IL-21的产生，IL-21是类转换B细胞抗体至关重要的细胞因子。这些研究为人类基因组中与SLE相关的调节体系提供了机械的见解。