Blmpf1^C3H/Kam
QTL Variant Detail

Summary

• QTL variant: Blmpf1^C3H/Kam
• Name: bleomycin-induced pulmonary fibrosis 1; C3H/Kam
• MGI ID: MGI:2668893
• QTL: Blmpf1 Location: Chr17:32061652-37644775 bp Genetic Position: Chr17, cM position of peak correlated region/allele: 17.25 cM
• QTL Note: genome coordinates based on the boundaries of the QTL region

Variant origin

• Strain of Specimen: C3H/Kam

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers decreased incidence of bleomycin-induced lung fibrosis compared to C57BL/6J.
• Inheritance: Other (see notes)

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

Candidate Genes

J:100369

Gene expression analysis was used to identify candidate genes for bleomycin-induced pulmonary fibrorsis QTLs Blmpf1 and Blmpf2. These loci were previously mapped in an F2 cross between susceptible strain C57BL/6J and resistant strain C3Hf/Kam. Blmpf1 maps to 17.4 cM on mouse Chromosome 17 and Blmpf2 maps to 28 cM on mouse Chromosome 11.

Genes mapping to the Blmpf1 interval on mouse Chromosome 17 were evaluated for lung mRNA expression in C57BL/6J and C3Hf/Kam animals with and without bleomycin treatment. Genes showing significant expression differences with P<0.001 are H2-D1 (19.09 cM), C4 (18.8 cM), Glo1 (16 cM), H2-Q7 (19.19 cM), H2-K (18.65 cM), Gabbr1 (20.4 cM), Tff2 (17 cM), Notch4 (18.72 cM), and Fkbp5 (13 cM).

Genes mapping to the Blmpf2 interval on mouse Chromosome 11 were evaluated for lung mRNA expression in C57BL/6J and C3Hf/Kam animals with and without bleomycin treatment. Genes showing significant expression differences with P<0.001 are Scgb3a1 (25 cM), Trim16, Pttg1, and Gria1 (31 cM).

Mapping and Phenotype information for this QTL, its variants and associated markers

J:78423

Genome scan using 190 polymorphic markers at an average spacing of 10 cM was performed on a population of (C57BL/6J x C3Hf/Kam)F2 intercross animals to identify QTLs associated with susceptibility to bleomycin-induced pulmonary fibrosis. Parental strain C57BL/6J is susceptible to bleomycin- induced pulmonary fibrosis whereas parental strain C3Hf/Kam is resistant.

A major locus named Blmpf1 mapped to 17.4 cM (in the H2 region) on mouse Chromosome 17 with peak linkage at D17Mit16 (LOD=17.4). The QTL interval of Blmpf1 was narrowed to a 2.7 cM region between D17Mit175 (17.7 cM) and D17Mit148 (20.4 cM) using a congenic strain designated C3H.SW-H2b.C3H-D17Mit175-D17Mit47. This locus exhibits additive inheritance with C57BL/6J-derived alleles conferring increased incidence of bleomycin-induced pulmonary fibrosis. Blmpf1 explains about 20% of the phenotypic variance. Tnf maps near Blmpf1 and may be a possible candidate gene.

Blmpf2 is a male-specific locus and maps to 28 cM on mouse Chromosome 11 with peak linkage at D11Mit272 (LOD=5.6). The QTL range of Blmpf2 spans 24 cM - 37 cM and is flanked by D11Mit310 and D11Mit5. The C3Hf/Kam-derived allele confers decreased lung fibrosis severity in male animals at Blmpf2. The locus also interacts with Blmpf1 and exhibits additive inheritance. Male animals homozygous for C57BL/6J-derived alleles at both Blmpf1 and Blmpf2 show increased incidence of bleomycin- induced pulmonary fibrosis compared to doubly heterozygous animals. Blmpf2 explains about 8.9% of the phenotypic variance. The activity of Blmh shows a correlation to the phenotype and is considered a viable candidate gene.

A suggestive QTL was detected on mouse Chromosome 8 with a LOD score of 2.78 at D8Mit242 and D8Mit271.

References

• Original: J:78423 Haston CK, et al., Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice. Hum Mol Genet. 2002 Aug 1;11(16):1855-63
• All: 1 reference(s)