Table 1.
Apabetalone downregulates transcriptional targets of inflammatory mediators in the CAD patient plasma as predicted by IPA® “canonical pathway” and “upstream regulators” analysis.
| Ingenuity® Pathway Analysis | Pathway/regulatora | Activation z-scoreb | p value of overlapc | Target molecules in dataset (gene symbols)d |
|---|---|---|---|---|
| Canonical pathway | APR signaling | -2.1 | 2.4 × 10−10 | C4A/C4B, C3, IL1RN, CRP, MAPK9, FGA/FGB/FGG, AGT |
| Upstream regulators | LPS | -3.1 | 8.9 × 10−13 | ADIPOQ, AGT, BCL6, C3, CCL18, CCL5, CDH1, CDH5, CRP, CSF1R, EREG, FGA/FGB/FGG, IL1RN, IL2, KIT, MAPK9, MB, MMP10, NCR3, POMC, SPP1, TIMP2, TNFSF14, VTN |
| Upstream regulators | IL-6 | -2.6 | 7.1 × 10−15 | AGT, BCL6, C3, CCL5, CDH1, CDKN1B, CRP, EREG, FGA/FGB/FGG, GCG, IGFBP6, IL1RN, IL2, KIT, MMP10, POMC, SPP1 |
| Upstream regulators | IFNG | -2.6 | 2.5 × 10−10 | ADIPOQ, AGT, C3, C4A/C4B, CCL18, CCL5, CDH1, CDKN1B, CSF1R, CTSD, ERAP1, FGA/FGB/FGG, IL1RN, IL2, MMP10, NCR3, POMC, SPP1, TNFSF12 |
| Upstream regulators | OSM | -2.0 | 6.5 × 10−7 | CCL5, SPP1, MMP10, IGFBP6, FGA/FGB/FGG, CDKN1B, CDH1, CRP, POMC |
| Upstream regulators | IL1A | -2.0 | 2.0 × 10−6 | CCL5, IL1RN, IL2, KIT, MMP10, POMC, SPP1 |
| Upstream regulators | NFKB1 | -1.8 | 5.2 × 10−5 | CCL5, CRP, FGA/FGB/FGG, IL1RN, IL2, MMP10 |
Plasma proteins affected by apabetalone treatment by more than 10% (versus placebo, p < 0.05) were analyzed with the IPA® “canonical pathway” and “upstream regulator” analytics. aAPR: acute phase response; LPS: lipopolysaccharide; IL-6: interleukin 6; IFNG: interferon γ; OSM: oncostatin M; IL1A: interleukin 1α; NFKB1: nuclear factor κB subunit 1. bIPA® z-score compares the observed differential regulation of a gene in the dataset to changes predicted by the literature which can be either “activating” or “inhibiting.” z − score < −2 predicts downregulation within a gene set associated with a transcriptional regulator. cThe overlap p value measures whether there is a statistically significant overlap between the dataset genes and the genes that are regulated by a transcriptional regulator. It is calculated using Fisher's exact test, and significance is attributed to p values < 0.01. dApabetalone target proteins that contribute to IPA® “canonical pathways” or “upstream regulators” are listed as gene symbols.