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Introduction: Genome-wide association studies revealed a robust association between genetic variants at the LIPA (lysosomal acid lipase) locus and coronary artery diseases (CAD). eQTL studies support that the risk alleles of LIPA CAD variants are associated with higher LIPA mRNA and enzyme activity in human monocytes, but not other blood or vascular cells, suggesting that increased myeloid LIPA may confer CAD risk. Herein, we aim to establish the causality of the variant-to-function relationship for the LIPA locus and elucidate how increased myeloid LIPA impact atherosclerosis in vivo. Hypothesis: We hypothesized that causal variants in LIPA lead to increased LIPA expression and enzyme activity in macrophages and myeloid-specific overexpression of Lipa promotes atherosclerosis. Results: We first confirmed that in human monocyte-derived macrophages, LIPA mRNA, protein and enzyme activity are higher in the risk allele carriers of CAD variants. High-resolution HiC revealed an intronic enhancer region showing strong interaction with the LIPA promoter. Within the enhancer region, both rs1320496 and rs1412445 had independent association with CAD and their risk alleles led to increased enhancer activity measured by luciferase assay. Risk allele of rs1320496 also demonstrated increased binding for PU.1, a myeloid-specific transcription factor. To establish how increased myeloid LIPA impact atherosclerosis, we generated myeloid-specific Lipa overexpression mice ( Lipa Tg , Ldlr -/- ). Lipa Tg significantly increased atherosclerotic lesion size without affecting plasma cholesterol level. scRNA-seq analysis showed that Lipa Tg led to reduced lipid-enriched yet increased inflammatory macrophage subsets, and upregulation of genes in chemokine signaling. This is further confirmed by reduced neutral lipid accumulation in both plaque and peritoneal macrophages in Lipa Tg mice. Mechanistically, Lipa Tg led to reduced expression of modified-LDL receptors, increased expression of inflammatory chemokines, and increased circulating IL18 and CXCL2 that likely drive immune cells infiltration during atherosclerosis. Conclusions: We for the first time established that LIPA risks alleles drive increased myeloid LIPA and aggravate atherosclerosis.