Systems Approach to Integrating Preclinical Apolipoprotein E-Knockout Investigations Reveals Novel Etiologic Pathways and Master Atherosclerosis Network in Humans

Objective:Animal models of atherosclerosis are used extensively to interrogate molecular mechanisms in serial fashion. We tested whether a novel systems biology approach to integration of preclinical data identifies novel pathways and regulators in human disease.Approach and Results:Of 716 articles published inATVBfrom 1995 to 2019 using the apolipoprotein E knockout mouse to study atherosclerosis, data were extracted from 360 unique studies in which a gene was experimentally perturbed to impact plaque size or composition and analyzed using Ingenuity Pathway Analysis software. TREM1 (triggering receptor expressed on myeloid cells) signaling and LXR/RXR (liver X receptor/retinoid X receptor) activation were identified as the top atherosclerosis-associated pathways in mice (bothP−4, TREM1 implicated early and LXR/RXR in late atherogenesis). The top upstream regulatory network in mice (sc-58125, a COX2 inhibitor) linked 64.0% of the genes into a single network. The pathways and networks identified in mice were interrogated by testing for associations between the genetically predicted gene expression of each mouse pathway-identified human homolog with clinical atherosclerosis in a cohort of 88 660 human subjects. Homologous human pathways and networks were significantly enriched for gene-atherosclerosis associations (empiricalPPTGS2) with increased likelihood of atherosclerosis (odds ratio, 1.68 per SD of genetically predicted gene expression;P=1.07×10−6).Conclusions:PRESCIANT (Preclinical Science Integration and Translation) leverages published preclinical investigations to identify high-confidence pathways, networks, and regulators of human disease.