TY - JOUR
T1 - Identification of the Mhc region as an asthma susceptibility locus in recombinant congenic mice
AU - Nawijn, Martijn C.
AU - Piavaux, Benoit J.A.
AU - Jeurink, Prescilla V.
AU - Gras, Renée
AU - Reinders, Marjan A.
AU - Stearns, Timothy
AU - Foote, Simon
AU - Hylkema, Machteld N.
AU - Groot, Peter C.
AU - Korstanje, Ron
AU - Van Oosterhout, Antoon J.M.
PY - 2011/8/1
Y1 - 2011/8/1
N2 - Mouse models of allergic asthma are characterized by airway hyper-reactivity (AHR), Th2-driven eosinophilic airway inflammation, high allergen-specific IgE (anti-OVA IgE) levels in serum, and airway remodeling. Because asthma susceptibility has a strong genetic component, we aimed to identify new asthma susceptibility genes in the mouse by analyzing the asthma phenotypes of the Leishmania major resistant (lmr) recombinant congenic (RC) strains. The lmr RC strains are derived from C57BL/6 and BALB/c intercrosses and carry congenic loci on chromosome 17 (lmr1) and 9 (lmr2) in both backgrounds. Whereas the lmr2 locus on chromosome 9 contributes to a small background-specific effect on anti-OVA IgE and AHR, the lmr1 locusonchromosome17 mediatesa strong effectonTh2-driven eosinophilic airway inflammation and background-specific effects on anti-OVA IgE and AHR. The lmr1 locus contains almost 600 polymorphic genes. To narrowdownthis numberof candidate genes,we performed genome-wide transcriptional profiling on lung tissue from C.lmr1 RC mice and BALB/c control mice. We identified a small number of differentially expressed genes located within the congenic fragment, including a number of Mhc genes, polymorphic between BALB/c and C57Bl/6. The analysis of asthma phenotypes in the C.B10-H2b RC strain, carrying the C57Bl/6 haplotype of the Mhc locus in a BALB/c genetic background, reveals a strikingly similar asthma phenotype compared with C.lmr1, indicating that the differentially expressed genes located within the C.B10-H2b congenic fragment are the most likely candidate genes to contribute to the reduced asthma phenotypes associated with the C57Bl/6 allele of lmr1.
AB - Mouse models of allergic asthma are characterized by airway hyper-reactivity (AHR), Th2-driven eosinophilic airway inflammation, high allergen-specific IgE (anti-OVA IgE) levels in serum, and airway remodeling. Because asthma susceptibility has a strong genetic component, we aimed to identify new asthma susceptibility genes in the mouse by analyzing the asthma phenotypes of the Leishmania major resistant (lmr) recombinant congenic (RC) strains. The lmr RC strains are derived from C57BL/6 and BALB/c intercrosses and carry congenic loci on chromosome 17 (lmr1) and 9 (lmr2) in both backgrounds. Whereas the lmr2 locus on chromosome 9 contributes to a small background-specific effect on anti-OVA IgE and AHR, the lmr1 locusonchromosome17 mediatesa strong effectonTh2-driven eosinophilic airway inflammation and background-specific effects on anti-OVA IgE and AHR. The lmr1 locus contains almost 600 polymorphic genes. To narrowdownthis numberof candidate genes,we performed genome-wide transcriptional profiling on lung tissue from C.lmr1 RC mice and BALB/c control mice. We identified a small number of differentially expressed genes located within the congenic fragment, including a number of Mhc genes, polymorphic between BALB/c and C57Bl/6. The analysis of asthma phenotypes in the C.B10-H2b RC strain, carrying the C57Bl/6 haplotype of the Mhc locus in a BALB/c genetic background, reveals a strikingly similar asthma phenotype compared with C.lmr1, indicating that the differentially expressed genes located within the C.B10-H2b congenic fragment are the most likely candidate genes to contribute to the reduced asthma phenotypes associated with the C57Bl/6 allele of lmr1.
KW - Allergic asthma
KW - Chromosome 17
KW - Mouse model
KW - Quantitative trait locus
KW - Recombinant congenic mice
UR - http://www.scopus.com/inward/record.url?scp=80051613062&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2009-0369OC
DO - 10.1165/rcmb.2009-0369OC
M3 - Article
SN - 1044-1549
VL - 45
SP - 295
EP - 303
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
IS - 2
ER -