Genetic regulation of endotoxin-induced airway disease.
To identify novel genes regulating the biologic response to lipopolysaccharide (LPS), we used a combination of quantitative trait locus (QTL) analysis and microarray-based gene expression studies of C57BL/6J x DBA/2J(BXD) F2 and recombinant inbred (RI) mice. A QTL affecting pulmonary TNF-alpha production was identified on chromosome 2, and a region affecting both polymorphonuclear leukocyte recruitment and TNF-alpha levels was identified on chromosome 11. Microarray analyses of unchallenged and LPS-challenged BXD RI strains identified approximately 500 genes whose expression was significantly changed by inhalation of LPS. Of these genes, 28 reside within the chromosomal regions identified by the QTL analyses, implicating these genes as high priority candidates for functional studies. Additional high priority candidate genes were identified based on their differential expression in mice having high and low responses to LPS. Functional studies of these genes are expected to reveal important molecular mechanisms regulating the magnitude of biologic responses to LPS.
Cook
Donald N
DN
Department of Medicine, Duke University Medical Center, P.O. Box 2629, and the Durham VAMC, Durham, NC 27710, USA. donald.cook@duke.edu
Wang
Shuibang
S
Wang
Yonghong
Y
Howles
Gabriel P
GP
Whitehead
Gregory S
GS
Berman
Katherine G
KG
Church
Tony D
TD
Frank
Bryan C
BC
Gaspard
Renee M
RM
Yu
Yan
Y
Quackenbush
John
J
Schwartz
David A
DA
D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D005786:Gene Expression Regulation; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008171:Lung Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha