Decoding the Variant-to-Function Relationship for LIPA, a Risk Locus for CAD

Abstract

Translating human genomic discoveries into mechanistic insights requires linking genetic variations to candidate genes and their causal functional phenotypes. Genome-wide association studies have consistently identified LIPA as a risk locus for coronary artery disease (CAD), with previous expression quantitative trait loci (eQTL) analyses prioritizing LIPA as a candidate causal gene. However, functional studies elucidating the causal variants, regulatory mechanisms, target cell types, and their causal impact on atherosclerosis have been lacking. To address this gap, we applied functional genomics and experimental mouse models to establish the variant-to-function relationship at the LIPA locus. Our findings show that CAD risk alleles in the LIPA locus increase LIPA expression and enzyme activity specifically in monocytes/macrophages by enhancing PU.1 binding to an intronic enhancer region that interacts with the LIPA promoter. In myeloid Lipa-overexpressing mice, we observed larger atherosclerotic lesions accompanied by altered macrophage function, including increased macrophage accumulation due to enhanced monocyte recruitment, reduced neutral lipid accumulation, and upregulation of integrin and extracellular matrix pathways. Our work establishes a direct causal link between LIPA risk alleles and increased monocyte/macrophage LIPA that exacerbates atherosclerosis, bridging human functional genomic evidence to the mechanistic understanding of CAD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=58 SRC="FIGDIR/small/516293v2_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@11ce287org.highwire.dtl.DTLVardef@15c201aorg.highwire.dtl.DTLVardef@13f90c9org.highwire.dtl.DTLVardef@3aa3be_HPS_FORMAT_FIGEXP M_FIG C_FIG