Aliq4^A/J
QTL Variant Detail

Summary

• QTL variant: Aliq4^A/J
• Name: acute lung injury QTL 4; A/J
• MGI ID: MGI:2178601
• QTL: Aliq4 Location: Chr6:53273332-53273435 bp Genetic Position: Chr6, cM position of peak correlated region/allele: 25.82 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: A/J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers susceptibility to nickel-induced acute lung injury compared to C57BL/6J. (J:70966)
• Inheritance: Recessive

Notes

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

J:70966

Linkage analysis was performed on 307 (C57BL/6J x A/J) x A/J backcross animals to identify QTLs affecting nickel-induced acute lung injury. Parental strain A/J is sensitive to nickel-induced acute lung injury (as measured by mean survival time (MST) after exposure to nickel sulfate) whereas C57BL/6J is resistant. Significant linkage was detected at 26.5 cM on mouse Chromosome 6 near D6Mit183 with a LOD score of 3.0. This locus maps from 12 cM - 38 cM and was named Aliq4, acute lung injury QTL 4. C57BL/6J-derived alleles at Aliq4 confers increased mean survival time of animals exposed to nickel sulfate. Aliq4 also appears to interact additively with other loci on chromosomes 12, 16 and 9. Animals of haplotype H-H-H-AA at D6Mit183, D12Mit112, D16Mit152, and D9Mit299, respectively, exhibit a 52 hour MST longer than animals of haplotype AA-AA-AA-H. Positional candidate gene approach identified the following genes mapping near Aliq4 as potential candidate genes: Aqp1, Crhr2, Sftpb, Pecam, and Tgfa. Aliq4 alsomaps near a QTL for bronchial hyperresponsiveness, Bhr5, spanning 55 cM - 95 cM on mouse Chromosome 6.

J:83233

307 (C57BL/6J x A/J) x A/J backcross animals were screened for 77 microsatellite markers to identify QTLs affecting nickel-induced acute lung injury. Parental strain A/J is sensitive to nickel-induced acute lung injury (as measured by mean survival time (MST) after aerosol exposure to nickel sulfate) whereas C57BL/6J is resistant. Significant linkage was detected at 26.5 cM on mouse Chromosome 6 with a LOD score of 3.0 at D6Mit183. This locus is named Aliq4, acute lung injury QTL 4. Suggestive QTLs mapped to 25.7 cM on mouse Chromosome 1 with a LOD score of 2.5 at D1Mit213 and to 11 cM - 22 cM on mouse Chromosome 12 with a LOD score of 2.3 at D12Mit185 and D12Mit112. Microarray analysis was used to complement the QTL analysis by identifying genes differentially expressed between C57BL/6J and A/J as potential candidate genes. Sftpb is one such gene and maps near Aliq4 at 31 cM.

J:76106

109 extreme responders from an A/J x (C67BL/6J x A/J)F1 backcross were genotyped at 77 polymorphic loci to identify QTLs associated with NiSO4-induced lung injury. Parental strain C57BL/6J is resistant to NiSO4-induced lung injury compared to parental strain A/J.

A previously identified QTL, Aliq4, reached statistical significance in this study with LOD=3.0 at D6Mit183 at 26.5 cM on mouse Chromosome 6. The C57BL/6J-derived allele confers increased survival after NiSO4-induced lung injury by 12 hours compared to animals homozygous for A/J-derived alleles. Candidate genes for Aliq4 include Aqp1, Sftpb, and Tgfa.

Studies with transgenic animals overexpressing human TGFA (Tg(SFTPC-TGFA)1Kor on an FVB/N background) revealed increased survival time following NiSO4-induced lung injury compared to nontransgenic animals.

Suggestive linkage to NiSO4-induced lung injury mapped to 25.7 cM on mouse Chromosome 1 (LOD=2.5 near D1Mit213), 11 cM (LOD=2.3 at D12Mit185) and 22 cM (LOD=2.3 at D12Mit112) on mouse Chromosome 12, 22.5 cM on mouse Chromosome 8 (LOD=2.2 at D8Mit65), 23 cM on mouse Chromosome 9 (LOD=1.6 at D9Mit227), and 57 cM on mouse Chromosome 16 (LOD=1.6 at D16Mit152).

References

• Original: J:70966 Prows DR, et al., Quantitative trait analysis of nickel-induced acute lung injury in mice. Am J Respir Cell Mol Biol. 2001 Jun;24(6):740-6
• All: 4 reference(s)