title: Unraveling inflammatory responses using systems genetics and gene-environment interactions in macrophages.
abstract: 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.
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. ldorozco@mednet.ucla.edu
authors.forename: Luz D
authors.initials: LD
authors.lastname: Orozco
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bennett
authors.forename: Charles R
authors.initials: CR
authors.lastname: Farber
authors.forename: Anatole
authors.initials: A
authors.lastname: Ghazalpour
authors.forename: Calvin
authors.initials: C
authors.lastname: Pan
authors.forename: Nam
authors.initials: N
authors.lastname: Che
authors.forename: Pingzi
authors.initials: P
authors.lastname: Wen
authors.forename: Hong Xiu
authors.initials: HX
authors.lastname: Qi
authors.forename: Adonisa
authors.initials: A
authors.lastname: Mutukulu
authors.forename: Nathan
authors.initials: N
authors.lastname: Siemers
authors.forename: Isaac
authors.initials: I
authors.lastname: Neuhaus
authors.forename: Roumyana
authors.initials: R
authors.lastname: Yordanova
authors.forename: Peter
authors.initials: P
authors.lastname: Gargalovic
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Todd
authors.initials: T
authors.lastname: Kirchgessner
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D059647:Gene-Environment Interaction; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice / Q000235:genetics* / Q000276:immunology; D008815:Mice, Inbred Strains; D040641:Quantitative Trait Loci; D013045:Species Specificity; D013047:Specific Pathogen-Free Organisms; D049490:Systems Biology / Q000379:methods
chemical_list: D008070:Lipopolysaccharides