Chracterization_of_iPSC_derived_macrophages___cardiovascular_pilot_Open_access

Atherosclerosis is characterized by the aggregation of low-density lipoprotein (LDL) cholesterol in arterial walls. The uptake of modified LDL by macrophages leading to foam cell formation is critical to the initiation and progression of atherosclerotic lesions. The gene expression programs driving foam cell formation as well as their genetic determinants have not been characterized on the genome-wide level to date. Here, we differentiated induced pluripotent stem cells (iPSCs) derived from 70 healthy individuals into macrophages, followed by stimulation of iPSC-derived macrophages with acetylated LDL (acLDL). Using strand-specific RNA-sequencing, we identified 1,726 differentially expressed genes between resting and acLDL-treated macrophages, mapping to pro-inflammatory signaling and cholesterol biosynthesis pathways. We found the expression and splicing of 1,817 and 1,276 genes to be modulated by local genetic variants under acLDL stimulation, respectively. In addition, we defined 66 response-specific expression quantitative trait loci (QTLs), including the FCER1A and FADS2 gene regions, which have previously been associated with the regulation of inflammatory biomarkers and major lipids, respectively. Further, we identified 39 response-specific splicing QTLs, including the ANKRD9, FCGR2A and SIRPA gene regions. In summary, we have developed an experimental framework to map genotype-dependent gene expression and splicing changes in iPSC-derived macrophages dependent on acLDL exposure, many of which underlie genetic risk regions of cardiovascular disease and related traits.

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