Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers.
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.
Informatics and Analysis, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA. i_ming_wang@merck.com
I-Ming
IM
Wang
Bin
B
Zhang
Xia
X
Yang
Jun
J
Zhu
Serguei
S
Stepaniants
Chunsheng
C
Zhang
Qingying
Q
Meng
Mette
M
Peters
Yudong
Y
He
Chester
C
Ni
Deborah
D
Slipetz
Michael A
MA
Crackower
Hani
H
Houshyar
Christopher M
CM
Tan
Ernest
E
Asante-Appiah
Gary
G
O'Neill
Mingjuan Jane
MJ
Luo
Rolf
R
Thieringer
Jeffrey
J
Yuan
Chi-Sung
CS
Chiu
Pek Yee
PY
Lum
John
J
Lamb
Yves
Y
Boie
Hilary A
HA
Wilkinson
Eric E
EE
Schadt
Hongyue
H
Dai
Christopher
C
Roberts
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001499:Bayes Theorem; D020169:Caspases / Q000235:genetics / Q000276:immunology; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D015331:Cohort Studies; D019295:Computational Biology / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000235:genetics*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
D018925:Chemokines; D058847:Inflammasomes; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D020169:Caspases