Abhr2^A/J
QTL Variant Detail

Summary

• QTL variant: Abhr2^A/J
• Name: antigen-induced bronchial hyperresponsiveness 2; A/J
• MGI ID: MGI:2154928
• QTL: Abhr2 Location: unknown Genetic Position: Chr2, cM position of peak correlated region/allele: 22.83 cM
• QTL Note: genome coordinates based on the boundaries of the QTL region

Variant origin

• Strain of Specimen: A/J

Variant description

• Allele Type: QTL
• Inheritance: Not Specified

Notes

Two-way ANOVA analysis detected interaction between Abrh1 and Abhr2.

Hc (hemolytic complement) at 23.5 cM maps to the Abhr2 QTL interval and was identified as a candidate gene in a microarray analysis of lung mRNA from A/J, C3H/HeJ, and (A/J x C3H/HeJ)F1 x A/J backcross animals. The A/J allele of Hc has a 2 bp deletion resulting in deficient Hc mRNA and protein production, and is associated with susceptibility to allergen-induced bronchial hyperresponsiveness.

Candidate Genes

J:108211

Abhr2 (allergen induced bronchial hyperresponsiveness 2) is a previously identified QTL at approximately 30 cM on mouse Chromosome 2. Gene expression microarray analysis of lung RNA extracted from sensitive high-responder strain A/J and resistant low-responder strain C3H/HeJ, as well as low- and high-responding (A/J x C3H/HeJ)F1 x A/J backcross animals. Twenty-one differentially expressed genes were identified one of which, Hc (formerly C5), mapped near Abhr2 at 23.5 cM on chromosome 2. Hc mRNA expression patterns correlated with bronchial hyperresponsive phenotype- A/J and high-responder backcross animals exhibit high Hc expression whereas C3H/HeJ and low-responder backcross animals exhibit low Hc expression. In addition, Hc genotype also correlated with severity of bronchial hyperresponsiveness in backcross animals. Homozygosity for A/J-derived alleles at Hc was associated with high responsiveness while heterozygosity at Hc was associated with low responsiveness.

Hc SNP analysis revealed a 2 bp deletion in the sensitive A/J strain resulting in deficient Hc mRNA and protein production. Resistant strain C3H/HeJ does not have this mutation and produces functional Hc mRNA and protein. This SNP was screened in other inbred strains with known bronchial hyperresponsive phenotypes. The 2 bp Hc deletion was observed in sensitive strains AKR/J and A/J, but not in resistant strains C57BL/6J, BALB/cJ, and C3H/HeJ.

J:122917

The present study fine maps two previously identified airway hyper-responsiveness QTLs on mouse Chromosome 2 named Abhr1 (10 cM) and Abhr2 (30 cM). Thirty-seven polymorphic chromosome 2 markers were genotyped in 450 (C3H/HeJ x A/J)F1 x A/J backcross animals.

Mrc1 at 5 cM was identified as a potential candidate gene for Abhr1. Ptgs1 at 29 cM was identified as a potential candidate gene for Abhr2. Sequence analysis of Mrc1 and Ptgs1 sequences did not detect polymorphism between A/J and C3H/HeJ. Gene expression analysis of Mrc1 and Ptgs1 lung mRNA following induction of allergic asthma in A/J and C3H/HeJ animals was performed. Ptgs1 was found to be downregulated in both inbred strains 72 hours after allergic asthma induction; however a strain-specific expression difference was not detected.

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

J:66641

164 markers at an average density of 10cM was used to map QTLs associated with allergen-induced airway hyperresponsiveness (AHR) in a (C3H/HeJ x A/J)F1 x A/J backcross population, and the reciprocal backcross A/J x (C3H/HeJ x A/J)F1. Inbred strain A/J develops a high level of AHR when sensitized and challenged with allergen while inbred strain C3H/HeJ develops a low level of AHR. (C3H/HeJ x A/J)F1 animals exhibit an intermediate phenotype.

Abhr1 and Abhr2 are loci associated with AHR, both mapping to proximal mouse chromosome 2.

Abhr1 maps to a region flanked by D2Mit359 (5 cM) and D2Mit416 (10 cM) giving a peak LOD score of 4.2 at D2Mit416. Gata3 (7 cM), Il2rn (6.4 cM), Mrc1 (5 cM), and Il15ra (6.4 cM) are positional candidate genes in the region of Abhr1. Abhr1 is syntenic to human Chromosome 10p11-p13, 2q12-q14, and 9q22-q34.

Abhr2 maps to a region flanked by D2Mit238 (28 cM) and D2Mit298 (30 cM) giving a peak LOD score of 3.7 at D2Mit298. Hc (23.5 cM), Ptgs1 (29 cM), Ctsb-ps (31 cM), and Lcn2 (27 cM)are positional candidate genes in the region of Abhr2. Abhr2 is syntenic to human Chromosome 9q33-q34 and 2q14-q24.

A suggestive QTL, Abhr3, with a LOD of 1.9 mapped to a region of Chromosome 7 flanked by D7Mit21 (0.5 cM) and D7Mit56 (2.5 cM). Abhr3 is syntenic to human Chromosome 19q13.

Two-way ANOVA detected interaction between Abhr1 and Abhr2, but did not detect interaction between Abhr1 and Abhr3, or between Abhr2 and Abhr3.

References

• Original: J:66641 Ewart SL, et al., Quantitative trait loci controlling allergen-induced airway hyperresponsiveness in inbred mice. Am J Respir Cell Mol Biol. 2000 Oct;23(4):537-45
• All: 2 reference(s)