ObjectiveA recent genome-wide association study linked KLF2 as a novel Asian-specific locus for systemic lupus erythematosus (SLE) susceptibility. However, the underlying causal functional variant(s), cognate target gene(s) and genetic mechanisms associated with SLE risk are unknown.MethodsWe used bioinformatics to prioritise likely functional variants and validated the best candidate with diverse experimental techniques, including genome editing. Gene expression was compared between healthy controls (HCs) and patients with SLE with or without lupus nephritis (LN+, LN−).ResultsThrough bioinformatics and expression quantitative trait locus analyses, we prioritised rs4808485 in active chromatin, predicted to modulate KLF2 expression. Luciferase reporter assays and chromatin immunoprecipitation-qPCR demonstrated differential allele-specific enhancer activity and binding of active histone marks (H3K27ac, H3K4me3 and H3K4me1), Pol II, CTCF, P300 and the transcription factor PARP1. Chromosome conformation capture-qPCR revealed long-range chromatin interactions between rs4808485 and theKLF2 promoter.These were directly validated by CRISPR-based genetic and epigenetic editing in Jurkat and lymphoblastoid cells. Deleting the rs4808485 enhancer in Jurkat (KO) cells disrupted NLRP3 inflammasome machinery by reducingKLF2and increasingCASPASE1, IL-1βandGSDMDlevels. Knockout cells also exhibited higher proliferation and cell-cycle progression than wild type. RNA-seq validated interplay betweenKLF2and inflammasome machinery in HC, LN+ and LN−.ConclusionsWe demonstrate how rs4808485 modulates the inflammasome and cellular homoeostasis through regulatingKLF2expression. This establishes mechanistic connections between rs4808485 and SLE susceptibility.