Unraveling Inflammatory Responses using Systems Genetics and Gene-Environment Interactions in Macrophages

• Published in: Cell Vol. 151; no. 3; pp. 658 - 670
• Main Authors: Orozco, Luz D., Bennett, Brian J., Farber, Charles R., Ghazalpour, Anatole, Pan, Calvin, Che, Nam, Wen, Pingzi, Qi, Hong Xiu, Mutukulu, Adonisa, Siemers, Nathan, Neuhaus, Isaac, Yordanova, Roumyana, Gargalovic, Peter, Pellegrini, Matteo, Kirchgessner, Todd, Lusis, Aldons J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.10.2012
• Subjects: Animals; Cells, Cultured; chromosome mapping; chromosomes; Gene Knockdown Techniques; Gene-Environment Interaction; genes; genetic variation; hybrids; inflammation; Inflammation - immunology; lipopolysaccharides; Lipopolysaccharides - immunology; macrophages; Macrophages - immunology; Macrophages - metabolism; Male; mice; Mice - genetics; Mice - immunology; Mice, Inbred Strains; phospholipids; Quantitative Trait Loci; small interfering RNA; Species Specificity; Specific Pathogen-Free Organisms; Systems Biology - methods
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2012.08.043

Many common diseases have an important inflammatory component mediated in part by macrophages. Here we used a systems genetics strategy to examine the role of common genetic variation in macrophage responses to inflammatory stimuli. We examined genome-wide transcript levels in macrophages from 92 strains of the Hybrid Mouse Diversity Panel. We exposed macrophages to control media, bacterial lipopolysaccharide (LPS), or oxidized phospholipids. We performed association mapping under each condition and identified several thousand expression quantitative trait loci (eQTL), gene-by-environment interactions, and eQTL “hot spots” that specifically control LPS responses. We used siRNA knockdown of candidate genes to validate an eQTL hot spot in chromosome 8 and identified the gene 2310061C15Rik as a regulator of inflammatory responses in macrophages. We have created a public database where the data presented here can be used as a resource for understanding many common inflammatory traits that are modeled in the mouse and for the dissection of regulatory relationships between genes. [Display omitted] ▸ Systems genetics strategy to examine responses to inflammation in 92 mouse strains ▸ Genome-wide database of responses to acute versus chronic stimuli in macrophages ▸ Gene-environment interactions play a major role in the regulation of gene expression ▸ Validation of eQTL hot spot and identification of a novel regulator of inflammation A systems genetics strategy dissects macrophage responses to acute and chronic inflammatory stimuli in 92 mouse strains. Gene-environment interactions and eQTL hot spots identify an unknown regulator of inflammation.