Pulmonary adenoma susceptibility 1 (Pas1) locus affects inflammatory response.
Two outbred mouse lines, phenotypically selected for differential subcutaneous (s.c.) acute inflammatory response (AIR), were analysed for urethane-induced lung inflammatory response and susceptibility to lung tumorigenesis. AIR(min) mice, which show a low response to s.c. acute inflammation, developed a persistent subacute lung inflammatory response and a 40-fold higher lung tumor multiplicity than did AIR(max) mice, which are selected for high response to s.c. acute inflammation and showed a transient lung inflammatory response. A highly significant linkage disequilibrium pattern was observed in AIR(max) and AIR(min) mice at marker alleles located within a 452-kb pulmonary adenoma susceptibility 1 (Pas1) locus region, thus defining the location of gene candidacy for inflammatory response and for the biological effects of Pas1 in this region. AIR(min) and AIR(max) mice segregated by descent the Pas1(s) and Pas1(r) alleles, respectively, providing evidence for the involvement of the Pas1 locus in the inflammatory response. The 452-kb region contains Kras2 and four additional genes, including the lymphoid-restricted membrane protein (Lrmp) gene, whose Pro-->Leu nonconservative variation was linked with inflammatory response and Pas1 allelotype. These results provide a model to explore the mechanism underlying inherited predisposition to lung cancer in the context of a link to inflammation.
Maria
Durvanei Augusto
DA
Laboratório de Immunogenética, Instituto Butantan, São Paulo, Brazil.
Manenti
Giacomo
G
Galbiati
Federica
F
Ribeiro
Orlando Garcia
OG
Cabrera
Wafa Hanna Koury
WH
Barrera
Roberto Giannì
RG
Pettinicchio
Angela
A
De Franco
Marcelo
M
Starobinas
Nancy
N
Siqueira
Maria
M
Dragani
Tommaso A
TA
Ibañez
Olga Martinez
OM
D000236:Adenoma / Q000235:genetics*; D000818:Animals; D021461:Animals, Outbred Strains; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D011014:Pneumonia / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D040641:Quantitative Trait Loci; D018631:ras Proteins
D005819:Genetic Markers; C486311:IRAG2 protein, human; C117307:KRAS protein, human; C101764:Lrmp protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins