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

• DOI: 10.1161/atvbaha.121.317071
• Publication Date: 2021-11-11T10:00:21Z
• Authors: Megan M. Shuey; Rachel R. Xiang; M. Elizabeth Moss; Brigett V. Carvajal; Yihua Wang; Nicholas Camarda; Daniel Fabbri; Protiva Rahman; Jacob Ramsey; Alec Stepanian; Paola Sebastiani; Quinn S. Wells; Joshua A. Beckman; Iris Z. Jaffe
• Keywords: Liver X receptor; Retinoid X receptor; Biological pathway; Apolipoprotein E; Knockout mouse

Objective: Animal models of atherosclerosis are used extensively to interrogate molecular mechanisms in serial fashion. We tested whether a novel systems biology approach integration preclinical data identifies pathways and regulators human disease. Approach Results: Of 716 articles published ATVB from 1995 2019 using the apolipoprotein E knockout mouse study atherosclerosis, were extracted 360 unique studies which gene was experimentally perturbed impact plaque size or composition analyzed Ingenuity Pathway Analysis software. TREM1 (triggering receptor expressed on myeloid cells) signaling LXR/RXR (liver X receptor/retinoid receptor) activation identified as top atherosclerosis-associated mice (both P <1.93×10 − 4 , implicated early late atherogenesis). The upstream regulatory network (sc-58125, COX2 inhibitor) linked 64.0% genes into single network. networks interrogated by testing for associations between genetically predicted expression each pathway-identified homolog with clinical cohort 88 660 subjects. Homologous significantly enriched gene-atherosclerosis (empirical <0.01 network). This included 12(60.0%) pathway genes, 15(53.6%) 67(49.3%) genes. Mouse analyses predicted, validated, strong association ( PTGS2 ) increased likelihood (odds ratio, 1.68 per SD expression; =1.07×10 6 ). Conclusions: PRESCIANT (Preclinical Science Integration Translation) leverages investigations identify high-confidence pathways, networks,