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Identification of novel chromosomal regions associated with airway hyperresponsiveness in recombinant congenic strains of mice
Authors:Pierre Camateros  Rafael Marino  Anny Fortin  James G Martin  Emil Skamene  Rob Sladek  Danuta Radzioch
Institution:1. Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, H3A 2T5, Canada
2. Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada
3. Meakins-Christie Laboratories, McGill University, Montreal, QC, H2X 2P2, Canada
4. McGill University and Génome Québec Innovation Centre, Montréal, QC, H3A 1A4, Canada
5. Department of Human Genetics, McGill University, Montreal, QC, H3A 2T5, Canada
6. MGH-Research Institute, L11-218, 1650 Cedar Ave, Montreal, QC, H3G 1A4, Canada
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.
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