Advertisement

Mammalian Genome

, Volume 21, Issue 1–2, pp 28–38 | Cite as

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

  • Pierre Camateros
  • Rafael Marino
  • Anny Fortin
  • James G. Martin
  • Emil Skamene
  • Rob Sladek
  • Danuta RadziochEmail author
Article

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.

Keywords

Parental Strain Methacholine Airway Hyperresponsiveness Airway Responsiveness Potential Candidate Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

Supplementary material

335_2009_9236_MOESM1_ESM.doc (266 kb)
(DOC 266 kb)

References

  1. Ackerman KG, Huang H, Grasemann H, Puma C, Singer JB et al (2005) Interacting genetic loci cause airway hyperresponsiveness. Physiol Genomics 21:105–111CrossRefPubMedGoogle Scholar
  2. 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 31:373–374PubMedGoogle Scholar
  3. 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–D728CrossRefPubMedGoogle Scholar
  4. Busse WW, Lemanske RF Jr (2001) Asthma. N Engl J Med 344:350–362CrossRefPubMedGoogle Scholar
  5. 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 153:356–361PubMedGoogle Scholar
  6. Cockcroft DW, Killian DN, Mellon JJ, Hargreave FE (1977) Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 7:235–243CrossRefPubMedGoogle Scholar
  7. Daniels SE, Bhattacharrya S, James A, Leaves NI, Young A et al (1996) A genome-wide search for quantitative trait loci underlying asthma. Nature 383:247–250CrossRefPubMedGoogle Scholar
  8. 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 11:150–154CrossRefPubMedGoogle Scholar
  9. 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–L1123PubMedGoogle Scholar
  10. 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 14:487–495PubMedGoogle Scholar
  11. 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 23:537–545PubMedGoogle Scholar
  12. 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 98:10793–10798CrossRefPubMedGoogle Scholar
  13. 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 74:21–35CrossRefPubMedGoogle Scholar
  14. 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 31:410–421CrossRefPubMedGoogle Scholar
  15. 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 16:319–331CrossRefPubMedGoogle Scholar
  16. 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 161:113–124CrossRefPubMedGoogle Scholar
  17. 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 141:2–8PubMedGoogle Scholar
  18. Huh KH, Fuhrer C (2002) Clustering of nicotinic acetylcholine receptors: from the neuromuscular junction to interneuronal synapses. Mol Neurobiol 25:79–112CrossRefPubMedGoogle Scholar
  19. 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 1:221–226CrossRefPubMedGoogle Scholar
  20. 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 162:1255–1264CrossRefPubMedGoogle Scholar
  21. Krymskaya VP (2007) Targeting the phosphatidylinositol 3-kinase pathway in airway smooth muscle: rationale and promise. BioDrugs 21:85–95CrossRefPubMedGoogle Scholar
  22. Levitt RC, Mitzner W (1989) Autosomal recessive inheritance of airway hyperreactivity to 5-hydroxytryptamine. J Appl Physiol 67:1125–1132PubMedGoogle Scholar
  23. 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 2:1109–1116CrossRefPubMedGoogle Scholar
  24. Mihai C, Iscru DF, Druhan LJ, Elton TS, Agarwal G (2006) Discoidin domain receptor 2 inhibits fibrillogenesis of collagen type 1. J Mol Biol 361:864–876CrossRefPubMedGoogle Scholar
  25. Moffatt MF (2008) Genes in asthma: new genes and new ways. Curr Opin Allergy Clin Immunol 8:411–417CrossRefPubMedGoogle Scholar
  26. 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 33:407–411CrossRefPubMedGoogle Scholar
  27. 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 76:349–357CrossRefPubMedGoogle Scholar
  28. O’Byrne PM, Inman MD (2003) Airway hyperresponsiveness. Chest 123:411S–416SCrossRefPubMedGoogle Scholar
  29. 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 161:1836–1843PubMedGoogle Scholar
  30. 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 163:37–42PubMedGoogle Scholar
  31. 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 333:894–900CrossRefPubMedGoogle Scholar
  32. 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 12:1973–1979CrossRefPubMedGoogle Scholar
  33. 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 7:655–666CrossRefPubMedGoogle Scholar
  34. 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–D623CrossRefPubMedGoogle Scholar
  35. 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 17:331–344CrossRefPubMedGoogle Scholar
  36. 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 36:903–913CrossRefPubMedGoogle Scholar
  37. 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 85:666–671CrossRefPubMedGoogle Scholar
  38. 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 418:426–430CrossRefGoogle Scholar
  39. Vercelli D (2008) Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol 8:169–182CrossRefPubMedGoogle Scholar
  40. Wills-Karp M, Ewart SL (2004) Time to draw breath: asthma-susceptibility genes are identified. Nat Rev Genet 5:376–387CrossRefPubMedGoogle Scholar
  41. 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 100:3380–3385CrossRefPubMedGoogle Scholar
  42. 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 69:1271–1277CrossRefPubMedGoogle Scholar
  43. 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 8:601–605CrossRefPubMedGoogle Scholar
  44. Zosky GR, Sly PD (2007) Animal models of asthma. Clin Exp Allergy 37:973–988CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Pierre Camateros
    • 1
  • Rafael Marino
    • 1
  • Anny Fortin
    • 2
  • James G. Martin
    • 1
    • 3
  • Emil Skamene
    • 1
  • Rob Sladek
    • 1
    • 4
  • Danuta Radzioch
    • 1
    • 5
    • 6
    Email author
  1. 1.Division of Experimental Medicine, Department of MedicineMcGill UniversityMontrealCanada
  2. 2.Department of BiochemistryMcGill UniversityMontrealCanada
  3. 3.Meakins-Christie LaboratoriesMcGill UniversityMontrealCanada
  4. 4.McGill University and Génome Québec Innovation CentreMontréalCanada
  5. 5.Department of Human GeneticsMcGill UniversityMontrealCanada
  6. 6.MGH-Research InstituteMontrealCanada

Personalised recommendations