International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 169 - DISSECTING COMPLEX MULTIGENIC TRAITS BY MAPPING GENES THAT ACT SYSTEMICALLY THROUGH THEIR INFLUENCE ON MACROPHAGE CHARACTERISTICS

Fijneman RJA
VU University Medical Center, Amsterdam, the Netherlands

Co-Authors: 1) Vos M, 2) Demant P, 1) Kraal G
Institutions: 1) VU University Medical Center, Amsterdam, the Netherlands, 2) Roswell Park Cancer Institute, Buffalo, USA

Susceptibility to common diseases like cancer, atherosclerosis, infectious diseases and autoimmune diseases is influenced by multiple genetic factors. On the one hand, each of these diseases has its own distinct etiology and is therefore influenced by disease-specific susceptibility genes. On the other hand, some susceptibility genes may affect multiple diseases by functioning systemically. Our goal is to identify systemically-acting susceptibility genes by studying the genetics of macrophage characteristics because of the strong implications of macrophages in initiation and progression of various diseases. Bone marrow-derived macrophages (BMMf) were obtained from individual mice of F2-crosses produced between several OcB-9/Dem-derived inbred strains and their common background strain O20/A, resulting in segregation of about 10% of the genome that is known to contain 11 out of 30 previously mapped susceptibility to lung cancer (Sluc) loci. BMMf were subjected to a series of assays including stimulation with lipopolysaccharides upon which secretion of TNFα and IL-12p40 was measured by ELISA, and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 was determined by quantification of immunofluorescent staining. Here we report that two loci, Sluc6 and Sluc20, were significantly linked to secretion of TNFα and IL-12p40, and iNOS expression. Interestingly, both Sluc6 and Sluc20 are located within genomic regions that also influence lung tumor shape, susceptibility to intestinal cancer and autoimmune diseases, indicating that they might indeed affect multiple phenotypes. Future investigations aim to identify these 'macrophage-associated risk factors' upon which their influence on susceptibility to cancer and other diseases will be examined.


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