International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E26 Genetic and Functional Analysis of QTL that Modulate the Endotoxin-Induced Flammatory Response

L. E. Matesic, E. L. Niemitz, A. De Maio, and R. H. Reeves. Dept. of Physiology and Div. of Pediatric Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21205

The incidence of multiple organ dysfunction syndrome (MODS) is very high in patients after an episode of trauma, sepsis, pancreatitis or severe burns. MODS is believed to result from an exaggerated inflammatory response. Several previous studies suggest that the inflammatory response is genetically regulated. Two inbred strains of mice, C57BL/6J (B6) and A/J, showed differences in mortality, circulating cytokine levels and expression of acute phase genes within the liver after administration of E. coli lipopolysaccharide (LPS). In addition, B6 mice showed a significantly greater number of infiltrating polymorphonuclear leukocytes (PMN) in the liver 24 hours after i.p. injection of LPS (J. Hered. 89:525-530, 1998). The average number of PMN observed per high power magnification field was 51.05 15.51 in B6 mice (n=21) as compared to 13.76 5.31 in A/J mice (n=15, p<6.4X10-20). 123 progeny of an intercross of B6 and A/J were typed for PMN infiltration following challenge with LPS. A genome scan of these mice with 64 markers (one marker per 23 cM on average) identified six loci with suggestive or significant likelihood ratio statistic (LRS) scores using Map Manager QT. A locus on Chr13 reached the level of significant (LRS = 14.9, LOD equivalent 3.2) using free regression analysis or using a recessive model. Two loci mapped at the "suggestive" level on Chr 5; these same loci were detected independently by analysis of the AXB/BXA RI strain set. One of these Chr 5 loci includes a strong candidate gene encoding the cytokine, IL-6. We demonstrated previously that circulating levels of IL-6 are significantly higher in B6 than in A/J mice following LPS administration (Shock 10:319-323, 1998). IL-6 -/- mice are being assessed currently for LPS-induced PMN infiltration. Human homologs of candidate genes can be identified by comparative mapping, allowing us to study their possible contribution to the development of MODS.

Supported by NIH grant GM57317 and the Robert Garrett Research Foundation.

 


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