Abstract
Airway hyperresponsiveness is a key characteristic of human asthma and a marker for asthma–like conditions in animals. F1 mice derived from A/J and C57BL/6J display a phenotype which resembles the asthma–like phenotype of the A/J mice. Since airway responsiveness failed to segregate as a mendelian trait, we show significant linkage at two loci, Bhr1 (lod = 3.0) and Bhr2 (lod = 3.7) on chromosomes 2 and 15. A third locus, Bhr3 (lod = 2.83), maps to chromosome 17. Each of these loci maps near candidate loci implicated in the pathobiology of asthma. Our study represents the first linkages established through a genome–wide survey of airway hyperresponsiveness in any mammal.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hirshman, C.A., Downes, H. & Veith, L. Airway responses in offspring of dogs with and without airway hyperreactivity. J. appl. Physiol. 56, 1272–1277 (1984).
Konno, S. et al. Bronchial reactivity to methacholine and serotonin in serotonin inbred mouse strains. Arerugi 42, 42–47 (1993).
Levitt, R.C. & Mitzner, W. Expression of airway hyperreactivity to acetylcholine as a simple autosomal recessive trait in mice. FASEB J. 2, 2605–2608 (1988).
Levitt, R.C. & Mitzner, W. Autosomal recessive inheritance of airway hyperreactivity to 5-hydroxytryptamine. J. appl. Physiol. 67, 1125–1132 (1989).
Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute. National Asthma Education Program. Expert Panel Report. J. Allergy clin. Immunol. 88, 425–534 (1991).
Longo, G., Strinati, R., Poli, F. & Fumi, F. Genetic factors in nonspecific bronchial hyperreactivity. An epidemiologic study. Am. J. Dis. Child. 141, 331–334 (1987).
Nieminen, M.M. Unimodal distribution of bronchial hyperresponsiveness to methacholine in asthmatic patients. Chest 102, 1537–1543 (1992).
Lander, E.S. & Botstein, D. Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121, 185–199 (1989).
Broide, D.H. et al. Cytokines in symptomatic asthma airways. J. Allergy clin. Immunol. 89, 958–967 (1992).
Sim, T.C., Hilsmeier, K.A., Reece, L.M., Grant, J.A. & Alam, R. Interleukin-1 receptor antagonist protein inhibits the synthesis of IgE and proinf lammatory cytokines by allergen-stimulated mononuclear cells. Am. J. Respir. Cell. Mol. Biol. 11, 473–479 (1994).
Tsukagoshi, H., Sakamoto, T., Wenbing, X., Barnes, P.J. & Chung, K.F. Effect of interleukin-1b on airway hyperresponsiveness and inflammation in sensitized and nonsensitized Brown-Norway rats. J. Allergy clin. Immunol. 93, 464–9 (1994).
Gavett, S.H. & Wills-Karp, M. Elevated lung G protein levels and muscarinic receptor affinity in a mouse model of airway hyperreactivity. Am. J. Physiol. 265, L493–500 (1993).
Mikami, H. et al. Characteristics of two lines of guinea pigs (BHS and BHR) differing in bronchial sensitivity to acetylcholine and histamine exposure. Jikken Dobutsu 40, 453–460 (1991).
Barnes, P.J. Cytokines as mediators of chronic asthma. Am. J. resp. crit. Care Med. 150, S42–S49 (1994).
Aubert, J.D. et al. Platelet-derived growth factor and its receptor in lungs from patients with asthma and chronic airflow obstruction. Am. J. Physiol. 266, L655–663 (1994).
Gordon, J.R., Burd, P.R. & Galli, S.J. Mast cells as a source of multifunctional cytokines. Immunol. Today 11, 458–464 (1990).
Wasserman, S.I. Mast cell biology. J. Allergy clin. Immunol. 86, 590–593 (1990).
Pui, C.H. Serum interleukin-2 receptor: clinical and biological implications. Leukemia 3, 323–327 (1989).
Hashimoto, S. et al. Elevation of soluble IL-2 receptor and IL-4, and nonelevation of IFN-gamma in sera from patients with allergic asthma. Ann. Allergy 71, 455–458 (1993).
Park, C.S. et al. Soluble interleukin-2 receptor and cellular profiles in bronchoalveolar lavage fluid from patients with bronchial asthma. J. Allergy clin. Immunol. 91, 623–633 (1993).
Matsumoto, K., Taki, F., Miura, M., Matsuzaki, M. & Takagi, K. Serum levels of soluble IL-2R, IL-4, and soluble Fc epsilon Rll in adult bronchial asthma. Chest 105, 681–686 (1994).
Corrigan, C.J., Hartnell, A. & Kay, A.B. T lymphocyte activation in acute severe asthma. Lancet 1, 1129–1132 (1988).
Van Bever, H.P. et al. Effect of a bronchial provocation test with house-dust mite on blood eosinophilia, eosinophil cationic protein, soluble interleukin-2 receptor, and interleukin-6 in asthmatic children. Allergy 48, 443–449 (1993).
Sekizawa, K., Caughey, G.H., Lazarus, S.C., Gold, W.M. & Nadel, J.A. Mast cell tryptase causes airway smooth muscle hyperresponsiveness in dogs. J. clin. Invest. 83, 175–179 (1989).
Wenzel, S.E., Fowler, A.A.D. & Schwartz, L.B. Activation of pulmonary mast cells by bronchoalveolar allergen challenge. In vivo release of histamine and tryptase in atopic subjects with and without asthma. Am. Rev. respir. Dis. 137, 1002–1008 (1988).
Caughey, G.H., Leidig, F., Viro, N.F. & Nadel, J.A. Substance P and vasoactive intestinal peptide degradation by mast cell tryptase and chymase. J. Pharmacol. exp. Ther. 244, 133–137 (1988).
Lilly, C.M., Martins, M.A. & Drazen, J.M. Peptidase modulation of vasoactive intestinal peptide pulmonary relaxation in tracheal; superfused guinea pig lungs. J. clin. Invest. 91, 235–243 (1993).
Ruoss, S.J., Hartmann, T. & Caughey, G.H. Mast cell tryptase is a mitogen for cultured fibroblasts. J. clin. Invest. 88, 493–499 (1991).
Ying, S. et al. TNF alpha mRNA expression in allergic inflammation. Clin. exp. Allergy 21, 745–750 (1991).
Kips, J.C., Tavernier, J. & Pauwels, R.A. Tumor necrosis factor causes bronchial hyperresponsiveness in rats. Am. Rev. respir. Dis. 145, 332–336 (1992).
Martin, T.R. et al. Mast cell activation enhances airway responsiveness to methacholine in the mouse. J. clin. Invest. 91, 1176–1182 (1993).
Renz, H. et al. Aerosolized antigen exposure without adjuvant causes increased IgE production and increased airway responsiveness in the mouse. J. Allergy clin. Immunol. 89, 1127–1138 (1992).
Garsen, J., Nijkamp, F.P., Van Der Vliet, H. & Van Loveren, H. A role for cellular immunity in the induction of airway hyperresponsiveness induced by small molecular weight compounds. Toxicol. Lett. 72, 151–154 (1994).
Pauwels, R. et al. Genetic factors in non-specific bronchial reactivity in rats. Eur. J. respir. Dis. 66, 98–104 (1985).
Yarkony, K.A. & Wills-Karp, M. The effects of aging on airway hyperreactivity in inbred strains of mice. Am. Rev. respir. Dis. 147, A419 (1993).
Townley, R.G. et al. Segregation analysis of bronchial response to methacholine inhalation challenge in families with and without asthma. J. Allergy clin. Immunol. 77, 101–107 (1986).
Wright, S. Evolution and the Genetics of Populations: Genetic and Biometric Foundations. (University of Chicago Press, Chicago, 1968).
Martin, T.R., Gerard, N.P., Galli, S.J. & Drazen, J.M. Pulmonary responses to bronchoconstrictor agonists in the mouse. J. appl. Physiol. 64, 2318–2323 (1988).
Kroeker, J.P. Wiener analysis of nonlinear systems using Poisson-Charlier crosscorrelation. Biol. Cybernet 27, 221–227 (1977).
Lander, E.S. et al. MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics 1, 174–181 (1987).
Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual. (Cold Spring Harbor Laboratory, New York, 1989).
Dietrich, W.F. et al. A genetic map of the mouse with 4,006 simple sequence length polymorphisms. Nature Genet. 7, 220–45 (1994).
Paterson, A.H. et al. Mendelian factors underlying quantitative traits in tomato: comparison across species, generations, and environments. Genetics 127, 181–97 (1991).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
De Sanctis, G., Merchant, M., Beier, D. et al. Quantitative locus analysis of airway hyperresponsiveness in A/J and C57BL/6J mice. Nat Genet 11, 150–154 (1995). https://doi.org/10.1038/ng1095-150
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng1095-150
This article is cited by
-
A probiotic has differential effects on allergic airway inflammation in A/J and C57BL/6 mice and is correlated with the gut microbiome
Microbiome (2021)
-
Intranasal administration of budesonide-loaded nanocapsule microagglomerates as an innovative strategy for asthma treatment
Drug Delivery and Translational Research (2020)
-
Functional analysis of a novel ENU-induced PHD finger 11 (Phf11) mouse mutant
Mammalian Genome (2014)
-
Detection of loci for allergic asthma using SMXA recombinant inbred strains of mice
Immunogenetics (2013)
-
Genetic analysis of lung function in inbred mice suggests vitamin D receptor as a candidate gene
Molecular Genetics and Genomics (2011)