Immunogenetics

, Volume 65, Issue 1, pp 17–24 | Cite as

Detection of loci for allergic asthma using SMXA recombinant inbred strains of mice

  • Tamio Ohno
  • Masakazu Okamoto
  • Toru Hara
  • Naozumi Hashimoto
  • Kazuyoshi Imaizumi
  • Miyoko Matsushima
  • Masahiko Nishimura
  • Kaoru Shimokata
  • Yoshinori Hasegawa
  • Tsutomu Kawabe
Original Paper

Abstract

Asthma is regarded as a multifactorial inflammatory disorder arising as a result of inappropriate immune responses in genetically susceptible individuals to common environmental antigens. However, the precise molecular basis is unknown. To identify genes for susceptibility to three asthma-related traits, airway hyperresponsiveness (AHR), eosinophil infiltration, and allergen-specific serum IgE levels, we conducted a genetic analysis using SMXA recombinant inbred (RI) strains of mice. Quantitative trait locus analysis detected a significant locus for AHR on chromosome 17. For eosinophil infiltration, significant loci were detected on chromosomes 9 and 16. Although we could not detect any significant loci for allergen-specific serum IgE, analysis of consomic strains showed that chromosomes 17 and 19 carried genes that affected this trait. We detected genetic susceptibility loci that separately regulated the three asthma-related phenotypes. Our results suggested that different genetic mechanisms regulate these asthma-related phenotypes. Genetic analyses using murine RI and consomic strains enhance understanding of the molecular mechanisms of asthma in human.

Keywords

Airway hyperresponsiveness Asthma Eosinophil IgE Mouse QTL analysis 

Notes

Acknowledgments

The authors would like to thank Ms. Keiko Shimamoto and Ms. Ayako Asai for their technical assistance. Supported in part by a Grant-in-Aid for Scientific Research (Genome), Ministry of Education, Culture, Sports, Science and Technology, Japan.

References

  1. Ackerman KG, Huang H, Grasemann H, Puma C, Singer JB, Hill AE, Lander E, Nadeau JH, Churchill GA, Drazen JM, Beier DR (2005) Interacting genetic loci cause airway hyperresponsiveness. Physiol Genomics 21:103–111Google Scholar
  2. Anunciado RV, Ohno T, Mori M, Ishikawa A, Tanaka S, Horio F, Nishimura M, Namikawa T (2000) Distribution of body weight, blood insulin and lipid levels in the SMXA recombinant inbred strains and the QTL analysis. Exp Anim 49:217–224PubMedCrossRefGoogle Scholar
  3. Bauer AK, Malkinson AM, Kleeberger SR (2004) Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities. Am J Physiol Lung Cell Mol Physiol 287:L685–L703PubMedCrossRefGoogle Scholar
  4. Bradley A (2002) Mining the mouse genome. Nature 420:512–514PubMedCrossRefGoogle Scholar
  5. Daniels SE, Bhattacharrya S, James A, Leaves NI, Young A, Hill MR, Faux JA, Ryan GF, le Söuef PN, Lathrop GM, Musk AW, Cookson WO (1996) A genome-wide search for quantitative trait loci underlying asthma. Nature 383:247–250PubMedCrossRefGoogle Scholar
  6. De Sanctis GT, Merchant M, Beier DR, Dredge RD, Grobholz JK, Martin TR, Lander ES, Drazen JM (1995) Quantitative locus analysis of airway hyperresponsiveness in A/J and C57BL/6J mice. Nat Genet 11:150–154PubMedCrossRefGoogle Scholar
  7. De Sanctis GT, Singer JB, Jiao A, Yandava CN, Lee YH, Haynes TC, Lander ES, Beier DR, Drazen JM (1999) Quantitative trait locus mapping of airway responsiveness to chromosomes 6 and 7 in inbred mice. Am J Physiol 277:L1118–L1123PubMedGoogle Scholar
  8. Doerge RW, Churchill GA (1996) Permutation tests for multiple loci affecting a quantitative character. Genetics 142:285–294PubMedGoogle Scholar
  9. 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
  10. Ewart SL, Kuperman D, Schadt E, Tankersley C, Grupe A, Shubitowski DM, Peltz G, Wills-Karp M (2000) Quantitative trait loci controlling allergen-induced airway hyperresponsiveness in inbred mice. Am J Respir Cell Mol Biol 23:537–545PubMedGoogle Scholar
  11. Hizawa N, Freidhoff LR, Ehrlich E, Chiu YF, Duffy DL, Schou C, Dunston GM, Beaty TH, Marsh DG, Barnes KC, Huang SK (1998) Genetic influences of chromosomes 5q31–q33 and 11q13 on specific IgE responsiveness to common inhaled allergens among African American families. J Allergy Clin Immunol 102:449–453PubMedCrossRefGoogle Scholar
  12. Hopp RJ, Bewtra AK, Watt GD, Nair NM, Townley RG (1984) Genetic analysis of allergic disease in twins. J Allergy Clin Immunol 73:265–270PubMedCrossRefGoogle Scholar
  13. Ishih A, Ohno T, Nishimura M, Terada M (2000) Genetic analysis of mortality in murine angiostrongyliasis costaricensis using SMXA recombinant inbred mouse strains. Parasitol Int 49:335–338PubMedCrossRefGoogle Scholar
  14. Kobayashi M, Ohno T, Tsuji A, Nishimura M, Horio F (2003) Combinations of nondiabetic parental genomes elicit impaired glucose tolerance in mouse SMXA recombinant inbred strains. Diabetes 52:180–186PubMedCrossRefGoogle Scholar
  15. Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247PubMedCrossRefGoogle Scholar
  16. Longo G, Strinati R, Poli F, Fumi F (1987) Genetic factors in nonspecific bronchial hyperreactivity. An epidemiologic study. Am J Dis Child 141:331–334PubMedGoogle Scholar
  17. Masoli M, Fabian D, Holt S, Beasley R (2004) The global burden of asthma: executive summary of the GINA Dissemination Committee Report. Allergy 59:469–478PubMedCrossRefGoogle Scholar
  18. Moore KJ, Nagle DL (2000) Complex trait analysis in the mouse: the strengths, the limitations and the promise yet to come. Annu Rev Genet 34:653–686PubMedCrossRefGoogle Scholar
  19. Nadeau JH, Singer JB, Matin A, Lander ES (2000) Analysing complex genetic traits with chromosome substitution strains. Nat Genet 24:221–225PubMedCrossRefGoogle Scholar
  20. Nikolaidis NM, Zimmermann N, King NE, Mishra A, Pope SM, Finkelman FD, Rothenberg ME (2003) Trefoil factor-2 is an allergen-induced gene regulated by Th2 cytokines and STAT6 in the lung. Am J Respir Cell Mol Biol 29:458–464PubMedCrossRefGoogle Scholar
  21. Nishimura M, Hirayama N, Serikawa T, Kanehira K, Matsushima Y, Katoh H, Wakana S, Kojima A, Hiai H (1995) The SMXA: a new set of recombinant inbred strain of mice consisting of 26 substrains and their genetic profile. Mamm Genome 6:850–857PubMedCrossRefGoogle Scholar
  22. Ohno T, Katoh J, Kikkawa Y, Yonekawa H, Nishimura M (2003) Improved strain distribution patterns of SMXA recombinant inbred strains by microsatellite markers. Exp Anim 52:415–417PubMedCrossRefGoogle Scholar
  23. Okamoto M, Takeda K, Joetham A, Ohnishi H, Matsuda H, Swasey CH, Swanson BJ, Yasutomo K, Dakhama A, Gelfand EW (2008) Essential role of Notch signaling in effector memory CD8+ T cell-mediated airway hyperresponsiveness and inflammation. J Exp Med 205:1087–1097PubMedCrossRefGoogle Scholar
  24. Okamoto M, Matsuda H, Joetham A, Lucas JJ, Domenico J, Yasutomo K, Takeda K, Gelfand EW (2009) Jagged1 on dendritic cells and Notch on CD4+ T cells initiate lung allergic responsiveness by inducing IL-4 production. J Immunol 183:2995–3003PubMedCrossRefGoogle Scholar
  25. Pataer A, Nishimura M, Kamoto T, Ichioka K, Sato M, Hiai H (1997) Genetic resistance to urethan-induced pulmonary adenomas in SMXA recombinant inbred mouse strains. Cancer Res 57:2904–2908PubMedGoogle Scholar
  26. Piacentini S, Verrotti A, Polimanti R, Giannini C, Saccucci P, Manfellotto D, Fuciarelli M (2011) Functional polymorphism of GSTA1 and GSTO2 genes associated with asthma in Italian children. Clin Chem Lab Med 50:311–315PubMedGoogle Scholar
  27. Silver LM (1995) Mouse genetics: concepts and applications. Oxford University Press, New YorkGoogle Scholar
  28. Skadhauge LR, Christensen K, Kyvik KO, Sigsgaard T (1999) Genetic and environmental influence on asthma: a population-based study of 11,688 Danish twin pairs. Eur Respir J 13:8–14PubMedCrossRefGoogle Scholar
  29. Suzuki T, Ishikawa A, Nishimura M, Yoshimura T, Namikawa T, Ebihara S (2000) Mapping quantitative trait loci for circadian behavioral rhythms in SMXA recombinant inbred strains. Behav Genet 30:447–453PubMedCrossRefGoogle Scholar
  30. Tamachi T, Watanabe N, Oya Y, Kagami S, Hirose K, Saito Y, Iwamoto I, Nakajima H (2007) B and T lymphocyte attenuator inhibits antigen-induced eosinopil recruitment into the airways. Int Arch Allergy Immunol 143:50–55PubMedCrossRefGoogle Scholar
  31. Thim L, Madsen F, Poulsen SS (2002) Effect of trefoil factors on the viscoelastic properties of mucus gels. Eur J Clin Invest 32:519–527PubMedCrossRefGoogle Scholar
  32. Wakayama H, Hasegawa Y, Kawabe T, Saito H, Kikutani H, Shimokata K (1998) IgG-mediated anaphylaxis via Fc gamma receptor in CD40-deficient mice. Clin Exp Immunol 114:154–160PubMedCrossRefGoogle Scholar
  33. Wang S, Basten CJ, Zeng ZB (2003) Windows QTL cartographer 2.0. Department of Statistics, North Carolina State University, RaleighGoogle Scholar
  34. Weiss ST, Silverman EK (2011) Genome-wide association studies (GWAS) in asthma. Am J Respir Crit Care Med 184:631–633PubMedCrossRefGoogle Scholar
  35. Wills-Karp M (1999) Immunologic basis of antigen-induced airway hyperresponsiveness. Annu Rev Immunol 17:255–281PubMedCrossRefGoogle Scholar
  36. Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD (1998) Interleukin-13: central mediator of allergic asthma. Science 282:2258–2261PubMedCrossRefGoogle Scholar
  37. Yamashita N, Sekine K, Miyasaka T, Kawashima R, Nakajima Y, Nakano J, Yamamoto T, Horiuchi T, Hirai K, Ohta K (2001) Platelet-derived growth factor is involved in the augmentation of airway responsiveness through remodeling of airways in diesel exhaust particulate-treated mice. J Allergy Clin Immunol 107:135–142PubMedCrossRefGoogle Scholar
  38. Zeng ZB (1993) Theoretical basis for separation of multiple linked gene effects in mapping quantitative trait loci. Proc Natl Acad Sci USA 90:10972–10976PubMedCrossRefGoogle Scholar
  39. Zeng ZB (1994) Precision mapping of quantitative trait loci. Genetics 136:1457–1468PubMedGoogle Scholar
  40. Zhang Y, Lefort J, Kearsey V, Silva JR Le, Cookson WO, Vargaftig BB (1999) A genome-wide screen for asthma-associated quantitative trait loci in a mouse model of allergic asthma. Hum Mol Genet 8:601–605PubMedCrossRefGoogle Scholar
  41. Zimmermann N, King NE, Laporte J, Yang M, Mishra A, Pope SM, Muntel EE, Witte DP, Pegg AA, Foster PS, Hamid Q, Rothenberg ME (2003) Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J Clin Invest 111:1863–1874PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Tamio Ohno
    • 1
  • Masakazu Okamoto
    • 2
  • Toru Hara
    • 2
  • Naozumi Hashimoto
    • 2
  • Kazuyoshi Imaizumi
    • 2
  • Miyoko Matsushima
    • 3
  • Masahiko Nishimura
    • 1
  • Kaoru Shimokata
    • 2
  • Yoshinori Hasegawa
    • 2
  • Tsutomu Kawabe
    • 3
  1. 1.Division of Experimental AnimalsNagoya University Graduate School of MedicineNagoyaJapan
  2. 2.Department of Respiratory MedicineNagoya University Graduate School of MedicineNagoyaJapan
  3. 3.Department of Pathophysiological Laboratory SciencesNagoya University Graduate School of MedicineNagoyaJapan

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