Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

Association of the hCLCA1 gene with childhood and adult asthma

Genes & Immunity volume 5, pages 540–547 (2004)Cite this article

Abstract

Asthma is caused by bronchial inflammation. This inflammation involves mucus overproduction and hypersecretion. Recently, a mouse model of asthma showed that gob-5 is involved in the pathogenesis of asthma. The gob-5 gene is involved in mucus secretion and its expression is upregulated upon antigen attack in sensitized mice. The observation suggests that human homologue of gob-5, hCLCA1 (human calcium-dependent chloride channel-1), may be involved in human disease. We screened for single-nucleotide polymorphisms (SNPs) in hCLCA1 in the Japanese population. We identified eight SNPs, and performed association studies using 384 child patients with asthma, 480 adult patients with asthma, and 672 controls. In haplotype analysis, we found a different haplotype distribution pattern between controls and childhood asthma (P<0.0001) and between controls and adult asthma (P=0.0031). We identified a high-risk haplotype (CATCAAGT haplotype; P=0.0014) and a low-risk haplotype (TGCCAAGT haplotype; P=0.00010) in cases of childhood asthma. In diplotype analysis, patients who had the CATCAAGT haplotype showed a higher risk for childhood asthma than those who did not (P=0.0011). Individuals who had the TGCCAAGT haplotype showed a lower risk for childhood asthma than those who did not (P<0.0001). Our data suggested that variation of the hCLCA1 gene affects patients' susceptibility for asthma.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Daser A, Daheshia M, De Sanctis GT . Genetics of allergen-induced asthma. J Allergy Clin Immunol 2001; 108: 167–174.

    Article  CAS  PubMed  Google Scholar 

  2. McFadden ER, Gilbert IA . Asthma. N Engl J Med 1992; 327: 1928–1937.

    Article  PubMed  Google Scholar 

  3. Barnes PJ . New concepts in the pathogenesis of bronchial hyperresponsiveness and asthma. J Allergy Clin Immunol 1989; 83: 1013–1026.

    Article  CAS  PubMed  Google Scholar 

  4. Boushey HA, Fahy JV . Basic mechanisms of asthma. Environ Health Perspect 1995; 103: 229–233.

    PubMed  PubMed Central  Google Scholar 

  5. Barnes KC, Marsh DG . The genetics and complexity of allergy and asthma. Immunol Today 1998; 19: 325–332.

    Article  CAS  PubMed  Google Scholar 

  6. Steinke JW, Borish L, Rosenwasser LJ . 5. Genetics of hypersensitivity. J Allergy Clin Immunol 2003; 111: S495–S501.

    Article  CAS  PubMed  Google Scholar 

  7. Tattersfield AE, Knox AJ, Britton JR, Hall IP . Asthma. Lancet 2002; 360: 1313–1322.

    Article  CAS  PubMed  Google Scholar 

  8. Cookson WO, Moffatt MF . Genetics of asthma and allergic disease. Hum Mol Genet 2000; 9: 2359–2364.

    Article  CAS  PubMed  Google Scholar 

  9. Ono SJ . Molecular genetics of allergic diseases. Annu Rev Immunol 2000; 18: 347–366.

    Article  CAS  PubMed  Google Scholar 

  10. Nakanishi A, Morita S, Iwashita H et al. Role of gob-5 in mucus overproduction and airway hyperresponsiveness in asthma. Proc Natl Acad Sci USA 2001; 98: 5175–5180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhou Y, Dong Q, Louahed J et al. Characterization of a calcium-activated chloride channel as a shared target of Th2 cytokine pathways and its potential involvement in asthma. Am J Respir Cell Mol Biol 2001; 25: 486–491.

    Article  CAS  PubMed  Google Scholar 

  12. Toda M, Tulic MK, Levitt RC, Hamid Q . A calcium-activated chloride channel (HCLCA1) is strongly related to IL-9 expression and mucus production in bronchial epithelium of patients with asthma. J Allergy Clin Immunol 2002; 109: 246–250.

    Article  CAS  PubMed  Google Scholar 

  13. Hashimoto K, Graham BS, Ho SB et al. Respiratory syncytial virus in allergic lung inflammation increases Muc5ac and gob-5. Am J Respir Crit Care Med 2004; 170: 306–312.

    Article  PubMed  Google Scholar 

  14. Miller AL, Strieter RM, Gruber AD, Ho SB, Lukacs NW . CXCR2 regulates respiratory syncytial virus-induced airway hyperreactivity and mucus overproduction. J Immunol 2003; 170: 3348–3356.

    Article  CAS  PubMed  Google Scholar 

  15. Agnel M, Vermat T, Culouscou JM . Identification of three novel members of the calcium-dependent chloride channel (CaCC) family predominantly expressed in the digestive tract and trachea. FEBS Lett 1999; 455: 295–301.

    Article  CAS  PubMed  Google Scholar 

  16. Gruber AD, Elble RC, Ji HL, Schreur KD, Fuller CM, Pauli BU . Genomic cloning, molecular characterization, and functional analysis of human CLCA1, the first human member of the family of Ca2+-activated Cl− channel proteins. Genomics 1998; 54: 200–214.

    Article  CAS  PubMed  Google Scholar 

  17. Cunningham SA, Awayda MS, Bubien JK et al. Cloning of an epithelial chloride channel from bovine trachea. J Biol Chem 1995; 270: 31016–31026.

    Article  CAS  PubMed  Google Scholar 

  18. Elble RC, Widom J, Gruber AD et al. Cloning and characterization of lung-endothelial cell adhesion molecule-1 suggest it is an endothelial chloride channel. J Biol Chem 1997; 272: 27853–27861.

    Article  CAS  PubMed  Google Scholar 

  19. Zhu DZ, Cheng CF, Pauli BU . Mediation of lung metastasis of murine melanomas by a lung-specific endothelial cell adhesion molecule. Proc Natl Acad Sci USA 1991; 88: 9568–9572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Elble RC, Ji G, Nehrke K et al. Molecular and functional characterization of a murine calcium-activated chloride channel expressed in smooth muscle. J Biol Chem 2002; 277: 18586–18591.

    Article  CAS  PubMed  Google Scholar 

  21. Gandhi R, Elble RC, Gruber AD et al. Molecular and functional characterization of a calcium-sensitive chloride channel from mouse lung. J Biol Chem 1998; 273: 32096–32101.

    Article  CAS  PubMed  Google Scholar 

  22. Komiya T, Tanigawa Y, Hirohashi S . Cloning and identification of the gene gob-5, which is expressed in intestinal goblet cells in mice. Biochem Biophys Res Commun 1999; 255: 347–351.

    Article  CAS  PubMed  Google Scholar 

  23. Lee D, Ha S, Kho Y et al. Induction of mouse Ca(2+)-sensitive chloride channel 2 gene during involution of mammary gland. Biochem Biophys Res Commun 1999; 264: 933–937.

    Article  CAS  PubMed  Google Scholar 

  24. Pauli BU, Abdel-Ghany M, Cheng HC, Gruber AD, Archibald HA, Elble RC . Molecular characteristics and functional diversity of CLCA family members. Clin Exp Pharmacol Physiol 2000; 27: 901–905.

    Article  CAS  PubMed  Google Scholar 

  25. Gruber AD, Pauli BU . Molecular cloning and biochemical characterization of a truncated, secreted member of the human family of Ca2+-activated Cl− channels. Biochim Biophys Acta 1999; 1444: 418–423.

    Article  CAS  PubMed  Google Scholar 

  26. Gruber AD, Schreur KD, Ji HL, Fuller CM, Pauli BU . Molecular cloning and transmembrane structure of hCLCA2 from human lung, trachea, and mammary gland. Am J Physiol 1999; 276: C1261–C1270.

    Article  CAS  PubMed  Google Scholar 

  27. Gruber AD, Pauli BU . Clustering of the human CLCA gene family on the short arm of chromosome 1 (1p22–31). Genome 1999; 42: 1030–1032.

    Article  CAS  PubMed  Google Scholar 

  28. Hasegawa K, Tamari M, Shao C et al. Variations in the C3, C3aR and C5 genes affect risk for bronchial asthma and related phenotypes. Hum Genet 27 July 2004 (Epub ahead of print). DOI: 10.1007/s00439-004-1157-z.

  29. Hirakawa M, Tanaka T, Hashimoto Y, Kuroda M, Takagi T, Nakamura Y . JSNP: a database of common gene variations in the Japanese population. Nucleic Acids Res 2002; 30: 158–162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lewontin RC . The interaction of selection and linkage. I. General considerations; heterotic models. Genetics 1964; 49: 49–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Hill WG, Robertson A . Linkage disequilibrium in finite populations. Theor Appl Genet 1968; 38: 226–231.

    Article  CAS  PubMed  Google Scholar 

  32. Niimi T, Munakata M, Keck-Waggoner CL et al. A polymorphism in the human UGRP1 gene promoter that regulates transcription is associated with an increased risk of asthma. Am J Hum Genet 2002; 70: 718–725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Prokunina L, Castillejo-Lopez C, Oberg F et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002; 32: 666–669.

    Article  CAS  PubMed  Google Scholar 

  34. Hegab AE, Sakamoto T, Uchida Y et al. CLCA1 gene polymorphisms in chronic obstructive pulmonary disease. J Med Genet 2004; 41: e27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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 1991; 88: 425–534.

  36. Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute. Second expert panel on the management of asthma Publication 1997, 97-4051A.

  37. Lyamichev V, Mast AL, Hall JG et al. Polymorphism identification and quantitative detection of genomic DNA by invasive cleavage of oligonucleotide probes. Nat Biotechnol 1999; 17: 292–296.

    Article  CAS  PubMed  Google Scholar 

  38. Mein CA, Barratt BJ, Dunn MG et al. Evaluation of single nucleotide polymorphism typing with invader on PCR amplicons and its automation. Genome Res 2000; 10: 330–343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fujii K, Matsubara Y, Akanuma J et al. Mutation detection by TaqMan-allele specific amplification: application to molecular diagnosis of glycogen storage disease type Ia and medium-chain acyl-CoA dehydrogenase deficiency. Hum Mutat 2000; 15: 189–196.

    Article  CAS  PubMed  Google Scholar 

  40. Ohnishi Y, Tanaka T, Ozaki K, Yamada R, Suzuki H, Nakamura Y . A high-throughput SNP typing system for genome-wide association studies. J Hum Genet 2001; 46: 471–477.

    Article  CAS  PubMed  Google Scholar 

  41. Brown CC . The validity of approximation methods for interval estimation of the odds ratio. Am J Epidemiol 1981; 113: 474–480.

    Article  CAS  PubMed  Google Scholar 

  42. Stephens M, Donnelly P . A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162–1169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Niu T, Qin ZS, Xu X, Liu JS . Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms. Am J Hum Genet 2002; 70: 157–169.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Drs Hiroko Endo, Reiko Takayanagi, Chifuyu Nakazawa (Department of Pediatrics, Tohoku Rosai Hospital, Sendai, Japan), Toshio Morikawa (Morikawa Children's clinic, Sendai), Miki Morikawa (Department of Pediatrics, JR Sendai Hospital), and Shigeaki Miyabayashi (Department of Pediatrics, Sendai National Hospital) for supporting our study. We thank all patients and their families, the volunteers who served as controls, and all staff members at the hospitals involved in this study. We also thank Ms Kumi Kato, Ms Yasuko Murayama, Mr Hiroshi Sekiguchi, and Ms Miki Kokubo for excellent technical assistance. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and grants from the Ministry of Health, Labor, and Welfare, Japan.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan

    F Kamada, Y Suzuki, C Shao, Y Aoki, S Kure & Y Matsubara

  2. Department of Respiratory and Infectious Diseases, Tohoku University School of Medicine, Sendai, Japan

    C Shao & G Tamura

  3. Laboratory for Genetics of Allergic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan

    M Tamari, K Hasegawa, T Hirota, M Shimizu, N Takahashi & T Shirakawa

  4. Department of Health Promotion and Human Behavior, Kyoto University School of Public Health, Kyoto, Japan

    X-Q Mao & T Shirakawa

  5. Osaka Prefectural Habikino Hospital, Osaka, Japan

    S Doi & H Fujiwara

  6. Miyatake Asthma Clinic, Osaka, Japan

    A Miyatake

  7. College of Nursing, University of Shiga, Shiga, Japan

    K Fujita

  8. Department of Pediatrics, Japanese Red Cross Sendai Hospital, Sendai, Japan

    Y Chiba

Authors
  1. F Kamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Tamari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Hasegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Hirota
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. X-Q Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Doi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A Miyatake
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. K Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Y Chiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Y Aoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. S Kure
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. G Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. T Shirakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Y Matsubara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Suzuki.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kamada, F., Suzuki, Y., Shao, C. et al. Association of the hCLCA1 gene with childhood and adult asthma. Genes Immun 5, 540–547 (2004). https://doi.org/10.1038/sj.gene.6364124

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364124

Keywords

This article is cited by

Search

Advanced search

Quick links