Skip to main content
SpringerLink
Log in

Identification of novel chromosomal regions associated with airway hyperresponsiveness in recombinant congenic strains of mice

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

Airway responsiveness is the ability of the airways to respond to bronchoconstricting stimuli by reducing their diameter. Airway hyperresponsiveness has been associated with asthma susceptibility in both humans and murine models, and it has been shown to be a complex and heritable trait. In particular, the A/J mouse strain is known to have hyperresponsive airways, while the C57BL/6 strain is known to be relatively refractory to bronchoconstricting stimuli. We analyzed recombinant congenic strains (RCS) of mice generated from these hyper- and hyporesponsive parental strains to identify genetic loci underlying the trait of airway responsiveness in response to methacholine as assessed by whole-body plethysmography. Our screen identified 16 chromosomal regions significantly associated with airway hyperresponsiveness (genome-wide P ≤ 0.05): 8 are supported by independent and previously published reports while 8 are entirely novel. Regions that overlap with previous reports include two regions on chromosome 2, three on chromosome 6, one on chromosome 15, and two on chromosome 17. The 8 novel regions are located on chromosome 1 (92–100 cM), chromosome 5 (>73 cM), chromosome 7 (>63 cM), chromosome 8 (52–67 cM), chromosome 10 (3–7 cM and >68 cM), and chromosome 12 (25–38 cM and >52 cM). Our data identify several likely candidate genes from the 16 regions, including Ddr2, Hc, Fbn1, Flt3, Utrn, Enpp2, and Tsc.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Ackerman KG, Huang H, Grasemann H, Puma C, Singer JB et al (2005) Interacting genetic loci cause airway hyperresponsiveness. Physiol Genomics 21:105–111

    Article  CAS  PubMed  Google Scholar 

  • Bates J, Irvin C, Brusasco V, Drazen J, Fredberg J et al (2004) The use and misuse of Penh in animal models of lung disease. Am J Respir Cell Mol Biol 31:373–374

    CAS  PubMed  Google Scholar 

  • Bult CJ, Eppig JT, Kadin JA, Richardson JE, Blake JA (2008) The Mouse Genome Database (MGD): mouse biology and model systems. Nucleic Acids Res 36:D724–D728

    Article  CAS  PubMed  Google Scholar 

  • Busse WW, Lemanske RF Jr (2001) Asthma. N Engl J Med 344:350–362

    Article  CAS  PubMed  Google Scholar 

  • Carey VJ, Weiss ST, Tager IB, Leeder SR, Speizer FE (1996) Airways responsiveness, wheeze onset, and recurrent asthma episodes in young adolescents. The East Boston Childhood Respiratory Disease Cohort. Am J Respir Crit Care Med 153:356–361

    CAS  PubMed  Google Scholar 

  • Cockcroft DW, Killian DN, Mellon JJ, Hargreave FE (1977) Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 7:235–243

    Article  CAS  PubMed  Google Scholar 

  • Daniels SE, Bhattacharrya S, James A, Leaves NI, Young A et al (1996) A genome-wide search for quantitative trait loci underlying asthma. Nature 383:247–250

    Article  CAS  PubMed  Google Scholar 

  • De Sanctis GT, Merchant M, Beier DR, Dredge RD, Grobholz JK et al (1995) Quantitative locus analysis of airway hyperresponsiveness in A/J and C57BL/6J mice. Nat Genet 11:150–154

    Article  PubMed  Google Scholar 

  • De Sanctis GT, Singer JB, Jiao A, Yandava CN, Lee YH et al (1999) Quantitative trait locus mapping of airway responsiveness to chromosomes 6 and 7 in inbred mice. Am J Physiol 277:L1118–L1123

    PubMed  Google Scholar 

  • Ewart SL, Mitzner W, DiSilvestre DA, Meyers DA, Levitt RC (1996) Airway hyperresponsiveness to acetylcholine: segregation analysis and evidence for linkage to murine chromosome 6. Am J Respir Cell Mol Biol 14:487–495

    CAS  PubMed  Google Scholar 

  • Ewart SL, Kuperman D, Schadt E, Tankersley C, Grupe A et al (2000) Quantitative trait loci controlling allergen-induced airway hyperresponsiveness in inbred mice. Am J Respir Cell Mol Biol 23:537–545

    CAS  PubMed  Google Scholar 

  • Fortin A, Cardon LR, Tam M, Skamene E, Stevenson MM et al (2001a) Identification of a new malaria susceptibility locus (Char4) in recombinant congenic strains of mice. Proc Natl Acad Sci USA 98:10793–10798

    Article  CAS  PubMed  Google Scholar 

  • Fortin A, Diez E, Rochefort D, Laroche L, Malo D et al (2001b) Recombinant congenic strains derived from A/J and C57BL/6J: a tool for genetic dissection of complex traits. Genomics 74:21–35

    Article  CAS  PubMed  Google Scholar 

  • Ganguly K, Stoeger T, Wesselkamper SC, Reinhard C, Sartor MA et al (2007) Candidate genes controlling pulmonary function in mice: transcript profiling and predicted protein structure. Physiol Genomics 31:410–421

    Article  CAS  PubMed  Google Scholar 

  • Gill K, Boyle AE (2005a) Genetic analysis of alcohol intake in recombinant inbred and congenic strains derived from A/J and C57BL/6J progenitors. Mamm Genome 16:319–331

    Article  CAS  PubMed  Google Scholar 

  • Gill KJ, Boyle AE (2005b) Quantitative trait loci for novelty/stress-induced locomotor activation in recombinant inbred (RI) and recombinant congenic (RC) strains of mice. Behav Brain Res 161:113–124

    Article  CAS  PubMed  Google Scholar 

  • Hopp RJ, Townley RG, Biven RE, Bewtra AK, Nair NM (1990) The presence of airway reactivity before the development of asthma. Am Rev Respir Dis 141:2–8

    CAS  PubMed  Google Scholar 

  • Huh KH, Fuhrer C (2002) Clustering of nicotinic acetylcholine receptors: from the neuromuscular junction to interneuronal synapses. Mol Neurobiol 25:79–112

    Article  CAS  PubMed  Google Scholar 

  • Karp CL, Grupe A, Schadt E, Ewart SL, Keane-Moore M et al (2000) Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat Immunol 1:221–226

    Article  CAS  PubMed  Google Scholar 

  • Kest B, Smith SB, Schorscher-Petcu A, Austin JS, Ritchie J et al (2009) Gnao1 (Galpha(O) protein) is a likely genetic contributor to variation in physical dependence on opioids in mice. Neuroscience 162:1255–1264

    Article  CAS  PubMed  Google Scholar 

  • Krymskaya VP (2007) Targeting the phosphatidylinositol 3-kinase pathway in airway smooth muscle: rationale and promise. BioDrugs 21:85–95

    Article  CAS  PubMed  Google Scholar 

  • Levitt RC, Mitzner W (1989) Autosomal recessive inheritance of airway hyperreactivity to 5-hydroxytryptamine. J Appl Physiol 67:1125–1132

    CAS  PubMed  Google Scholar 

  • McIntire JJ, Umetsu SE, Akbari O, Potter M, Kuchroo VK et al (2001) Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol 2:1109–1116

    Article  CAS  PubMed  Google Scholar 

  • Mihai C, Iscru DF, Druhan LJ, Elton TS, Agarwal G (2006) Discoidin domain receptor 2 inhibits fibrillogenesis of collagen type 1. J Mol Biol 361:864–876

    Article  CAS  PubMed  Google Scholar 

  • Moffatt MF (2008) Genes in asthma: new genes and new ways. Curr Opin Allergy Clin Immunol 8:411–417

    Article  PubMed  Google Scholar 

  • Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE et al (2003) Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 33:407–411

    Article  CAS  PubMed  Google Scholar 

  • Nicolae D, Cox NJ, Lester LA, Schneider D, Tan Z et al (2005) Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am J Hum Genet 76:349–357

    Article  CAS  PubMed  Google Scholar 

  • O’Byrne PM, Inman MD (2003) Airway hyperresponsiveness. Chest 123:411S–416S

    Article  PubMed  Google Scholar 

  • Palmer LJ, Burton PR, Faux JA, James AL, Musk AW et al (2000) Independent inheritance of serum immunoglobulin E concentrations and airway responsiveness. Am J Respir Crit Care Med 161:1836–1843

    CAS  PubMed  Google Scholar 

  • Palmer LJ, Rye PJ, Gibson NA, Burton PR, Landau LI et al (2001) Airway responsiveness in early infancy predicts asthma, lung function, and respiratory symptoms by school age. Am J Respir Crit Care Med 163:37–42

    CAS  PubMed  Google Scholar 

  • Postma DS, Bleecker ER, Amelung PJ, Holroyd KJ, Xu J et al (1995) Genetic susceptibility to asthma—bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 333:894–900

    Article  CAS  PubMed  Google Scholar 

  • Raby BA, Silverman EK, Lazarus R, Lange C, Kwiatkowski DJ et al (2003) Chromosome 12q harbors multiple genetic loci related to asthma and asthma-related phenotypes. Hum Mol Genet 12:1973–1979

    Article  CAS  PubMed  Google Scholar 

  • Roy MF, Riendeau N, Loredo-Osti JC, Malo D (2006) Complexity in the host response to Salmonella typhimurium infection in AcB and BcA recombinant congenic strains. Genes Immun 7:655–666

    Article  CAS  PubMed  Google Scholar 

  • Smith CM, Finger JH, Hayamizu TF, McCright IJ, Eppig JT et al (2007) The mouse Gene Expression Database (GXD): 2007 update. Nucleic Acids Res 35:D618–D623

    Article  CAS  PubMed  Google Scholar 

  • Thifault S, Ondrej S, Sun Y, Fortin A, Skamene E et al (2008) Genetic determinants of emotionality and stress response in AcB/BcA recombinant congenic mice and in silico evidence of convergence with cardiovascular candidate genes. Hum Mol Genet 17:331–344

    Article  CAS  PubMed  Google Scholar 

  • Torkamanzehi A, Boksa P, Ayoubi M, Fortier ME, Ng Ying Kin NM et al (2006) Identification of informative strains and provisional QTL mapping of amphetamine (AMPH)-induced locomotion in recombinant congenic strains (RCS) of mice. Behav Genet 36:903–913

    Article  PubMed  Google Scholar 

  • Tran T, Halayko AJ (2007) Extracellular matrix and airway smooth muscle interactions: a target for modulating airway wall remodelling and hyperresponsiveness? Can J Physiol Pharmacol 85:666–671

    Article  CAS  PubMed  Google Scholar 

  • Van EP, Little RD, Dupuis J, Del Mastro RG, Falls K et al (2002) Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418:426–430

    Article  Google Scholar 

  • Vercelli D (2008) Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol 8:169–182

    Article  CAS  PubMed  Google Scholar 

  • Wills-Karp M, Ewart SL (2004) Time to draw breath: asthma-susceptibility genes are identified. Nat Rev Genet 5:376–387

    Article  CAS  PubMed  Google Scholar 

  • Wiltshire T, Pletcher MT, Batalov S, Barnes SW, Tarantino LM et al (2003) Genome-wide single-nucleotide polymorphism analysis defines haplotype patterns in mouse. Proc Natl Acad Sci USA 100:3380–3385

    Article  CAS  PubMed  Google Scholar 

  • Xu X, Fang Z, Wang B, Chen C, Guang W et al (2001) A genomewide search for quantitative-trait loci underlying asthma. Am J Hum Genet 69:1271–1277

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Lefort J, Kearsey V, Lapa e Silva JR, Cookson WO et al (1999) A genome-wide screen for asthma-associated quantitative trait loci in a mouse model of allergic asthma. Hum Mol Genet 8:601–605

    Article  CAS  PubMed  Google Scholar 

  • Zosky GR, Sly PD (2007) Animal models of asthma. Clin Exp Allergy 37:973–988

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by grants from the Strategic Program for Asthma Research (SPAR) and the Canadian Institutes of Health Research (CIHR) awarded to Dr. D. Radzioch, a grant from Genome Quebec/Genome Canada awarded to Dr. E. Skamene, and a grant from Emerillon Therapeutics. R. Sladek is a Chercheur-boursier of the Fonds de la recherche en santé du Québec and the recipient of a MGH 175th Anniversary Award from the Research Institute of the Montreal General Hospital Foundation. P. Camateros and R. Marino are both supported by CIHR Doctoral Awards.

Author information

Authors and Affiliations

  1. Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, H3A 2T5, Canada

    Pierre Camateros, Rafael Marino, James G. Martin, Emil Skamene, Rob Sladek & Danuta Radzioch

  2. Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada

    Anny Fortin

  3. Meakins-Christie Laboratories, McGill University, Montreal, QC, H2X 2P2, Canada

    James G. Martin

  4. McGill University and Génome Québec Innovation Centre, Montréal, QC, H3A 1A4, Canada

    Rob Sladek

  5. Department of Human Genetics, McGill University, Montreal, QC, H3A 2T5, Canada

    Danuta Radzioch

  6. MGH-Research Institute, L11-218, 1650 Cedar Ave, Montreal, QC, H3G 1A4, Canada

    Danuta Radzioch

Authors
  1. Pierre Camateros
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rafael Marino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anny Fortin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James G. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Emil Skamene
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rob Sladek
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Danuta Radzioch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Danuta Radzioch.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(DOC 266 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Camateros, P., Marino, R., Fortin, A. et al. Identification of novel chromosomal regions associated with airway hyperresponsiveness in recombinant congenic strains of mice. Mamm Genome 21, 28–38 (2010). https://doi.org/10.1007/s00335-009-9236-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-009-9236-z

Keywords

Search

Navigation