|
|||||
|
|
Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers |
|
| Authors: | Jun Zhu Serguei Stepaniants Chunsheng Zhang Qingying Meng Mette Peters Yudong He Chester Ni Deborah Slipetz Michael A Crackower Hani Houshyar Christopher M Tan Ernest Asante‐Appiah Gary O'Neill Mingjuan Jane Luo Rolf Thieringer Jeffrey Yuan Chi‐Sung Chiu Pek Yee Lum John Lamb Yves Boie Hilary A Wilkinson Eric E Schadt Hongyue Dai Christopher Roberts |
| Institution: | 1. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, , New York, NY, USA;2. Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, , New York, NY, USA;3. Graduate School of Biological Sciences, Mount Sinai School of Medicine, , New York, NY, USA;4. Sage Bionetworks, , Seattle, WA, USA;5. Covance Genomics Laboratory, , Seattle, WA, USA;6. Informatics and Analysis, Merck Research Laboratories, Merck & Co., Inc., , West Point, PA, USA;7. Department of Integrative Biology and Physiology, University of California, , Los Angeles, CA, USA;8. Investigative Toxicology Department, Amgen, , Seattle, WA, USA;9. Systems Immunology, Benaroya Research Institute, , Seattle, WA, USA;10. Department of Respiratory and Inflammation, Merck Research Laboratories, Merck & Co., Inc., , Boston, MA, USA;11. In Vivo Pharmacology, Merck Research Laboratories, Merck & Co., Inc., , Boston, MA, USA;12. In Vivo Pharmacology, Merck Research Laboratories, Merck & Co., Inc., , Kenilworth, NJ, USA;13. Lilly Research Laboratories, Lilly Corporate Center, , Indianapolis, IN, USA;14. External Scientific Affairs, Merck Research Laboratories, Merck & Co., Inc., , Rahway, NJ, USA;15. World Wide Regulatory Affairs, Merck Research Laboratories, Merck & Co., Inc., , Rahway, NJ, USA;16. Product, Ayasdi Inc., , Palo Alto, CA, USA;17. Oncology Research Unit, Pfizer, , San Diego, CA, USA;18. Genomics Platform, Broad Institute, , Cambridge, MA, USA;19. Department of Respiratory and Inflammation, Merck Research Laboratories, Merck & Co., Inc., , Rahway, NJ, USA;20. Informatics and Analysis, Merck Research Laboratories, Merck & Co., Inc., , Boston, MA, USA |
| Abstract: | Common inflammatome gene signatures as well as disease‐specific signatures were identified by analyzing 12 expression profiling data sets derived from 9 different tissues isolated from 11 rodent inflammatory disease models. The inflammatome signature significantly overlaps with known drug targets and co‐expressed gene modules linked to metabolic disorders and cancer. A large proportion of genes in this signature are tightly connected in tissue‐specific Bayesian networks (BNs) built from multiple independent mouse and human cohorts. Both the inflammatome signature and the corresponding consensus BNs are highly enriched for immune response‐related genes supported as causal for adiposity, adipokine, diabetes, aortic lesion, bone, muscle, and cholesterol traits, suggesting the causal nature of the inflammatome for a variety of diseases. Integration of this inflammatome signature with the BNs uncovered 151 key drivers that appeared to be more biologically important than the non‐drivers in terms of their impact on disease phenotypes. The identification of this inflammatome signature, its network architecture, and key drivers not only highlights the shared etiology but also pinpoints potential targets for intervention of various common diseases. |
| Keywords: | Bayesian network co‐expression network inflammatome inflammatory diseases key regulators |