Gene-environment interactions in occupational asthma

  • Francine Kauffmann
  • Francesc Castro-Giner
  • Lidwien A. M. Smit
  • Rachel Nadif
  • Manolis Kogevinas
Part of the Progress in Inflammation Research book series (PIR)


This chapter reviews the existing knowledge regarding gene-environment interactions in occupational asthma. So far, studies have been conducted on relatively small samples, considering workers exposed to specific hazards such as isocyanates or red cedar. HLA class II, genes in the antioxidant defense, and more recently genes in the innate immunity pathway have been studied. As yet, few interactions have been demonstrated; however, the development of large-scale genetic studies of asthma will likely change the situation. Two types of approach can be developed based on testing hypotheses (candidate interactions) or in searching interactions with genes of yet-unknown function that may be evidenced through genome-wide associations. Current challenges concern the improvement of phenotypic and environmental characterization and setting up interdisciplinary research to understand the determinants of asthma. Building large international consortia on asthma with data on occupational exposure is warranted.


Occupational Exposure Allergy Clin Immunol Respir Crit Occupational Asthma Acid Anhydride 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cookson W (1999) The alliance of genes and environment in asthma and allergy. Nature 402: B5–11CrossRefPubMedGoogle Scholar
  2. 2.
    Ober C, Thompson EE (2005) Rethinking genetic models of asthma: The role of environmental modifiers. Curr Opin Immunol 17: 670–678CrossRefPubMedGoogle Scholar
  3. 3.
    Wenzel SE (2006) Asthma: Defining of the persistent adult phenotypes. Lancet 368: 804–813CrossRefPubMedGoogle Scholar
  4. 4.
    Strachan DP (2000) Family size, infection and atopy: The first decade of the “hygiene hypothesis”. Thorax 55 (Suppl 1): S2–10CrossRefGoogle Scholar
  5. 5.
    Zock JP, Plana E, Jarvis D, Anto JM, Kromhout H, Kennedy SM, Kunzli N, Villani S, Olivieri M, Toren K et al (2007) The use of household cleaning sprays and adult asthma: An international longitudinal study. Am J Respir Crit Care Med 176: 735–741CrossRefPubMedGoogle Scholar
  6. 6.
    Hudson KL, Holohan MK, Collins FS (2008) Keeping pace with the times — The Genetic Information Nondiscrimination Act of 2008. N Engl J Med 358: 2661–2663CrossRefPubMedGoogle Scholar
  7. 7.
    Van Hoyweghen I, Horstman K (2008) European practices of genetic information and insurance: Lessons for the Genetic Information Nondiscrimination Act. JAMA 300: 326–327CrossRefPubMedGoogle Scholar
  8. 8.
    Khoury MJ, Gwinn M, Yoon PW, Dowling N, Moore CA, Bradley L (2007) The continuum of translation research in genomic medicine: How can we accelerate the appropriate integration of human genome discoveries into health care and disease prevention? Genet Med 9: 665–674CrossRefPubMedGoogle Scholar
  9. 9.
    Schulte PA, Lomax GP, Ward EM, Colligan MJ (1999) Ethical issues in the use of genetic markers in occupational epidemiologic research. J Occup Environ Med 41: 639–646CrossRefPubMedGoogle Scholar
  10. 10.
    Balboni A, Baricordi OR, Fabbri LM, Gandini E, Ciaccia A, Mapp CE (1996) Association between toluene diisocyanate-induced asthma and DQB1 markers: A possible role for aspartic acid at position 57. Eur Respir J 9: 207–210CrossRefPubMedGoogle Scholar
  11. 11.
    Bernstein JA, Munson J, Lummus ZL, Balakrishnan K, Leikauf G (1997) T-cell receptor V beta gene segment expression in diisocyanate-induced occupational asthma. J Allergy Clin Immunol 99: 245–250CrossRefPubMedGoogle Scholar
  12. 12.
    Bignon JS, Aron Y, Ju LY, Kopferschmitt MC, Garnier R, Mapp C, Fabbri LM, Pauli G, Lockhart A, Charron D et al (1994) HLA class II alleles in isocyanate-induced asthma. Am J Respir Crit Care Med 149: 71–75PubMedGoogle Scholar
  13. 13.
    Kim SH, Oh HB, Lee KW, Shin ES, Kim CW, Hong CS, Nahm DH, Park HS (2006) HLA DRB1*15-DPB1*05 haplotype: A susceptible gene marker for isocyanate-induced occupational asthma? Allergy 61: 891–894CrossRefPubMedGoogle Scholar
  14. 14.
    Mapp CE, Beghe B, Balboni A, Zamorani G, Padoan M, Jovine L, Baricordi OR, Fabbri LM (2000) Association between HLA genes and susceptibility to toluene diisocyanateinduced asthma. Clin Exp Allergy 30: 651–656CrossRefPubMedGoogle Scholar
  15. 15.
    Rihs HP, Barbalho-Krolls T, Huber H, Baur X (1997) No evidence for the influence of HLA class II in alleles in isocyanate-induced asthma. Am J Ind Med 32: 522–527CrossRefPubMedGoogle Scholar
  16. 16.
    Mapp CE, Fryer AA, De Marzo N, Pozzato V, Padoan M, Boschetto P, Strange RC, Hemmingsen A, Spiteri MA (2002) Glutathione S-transferase GSTP1 is a susceptibility gene for occupational asthma induced by isocyanates. J Allergy Clin Immunol 109: 867–872CrossRefPubMedGoogle Scholar
  17. 17.
    Piirila P, Wikman H, Luukkonen R, Kaaria K, Rosenberg C, Nordman H, Norppa H, Vainio H, Hirvonen A (2001) Glutathione S-transferase genotypes and allergic responses to diisocyanate exposure. Pharmacogenetics 11: 437–445CrossRefPubMedGoogle Scholar
  18. 18.
    Wikman H, Piirila P, Rosenberg C, Luukkonen R, Kaaria K, Nordman H, Norppa H, Vainio H, Hirvonen A (2002) N-Acetyltransferase genotypes as modifiers of diisocyanate exposure-associated asthma risk. Pharmacogenetics 12: 227–233CrossRefPubMedGoogle Scholar
  19. 19.
    Bernstein DI, Wang N, Campo P, Chakraborty R, Smith A, Cartier A, Boulet LP, Malo JL, Yucesoy B, Luster M et al (2006) Diisocyanate asthma and gene-environment interactions with IL4RA, CD-14, and IL-13 genes. Ann Allergy Asthma Immunol 97: 800–806CrossRefPubMedGoogle Scholar
  20. 20.
    Ye YM, Kang YM, Kim SH, Kim CW, Kim HR, Hong CS, Park CS, Kim HM, Nahm DH, Park HS (2006) Relationship between neurokinin 2 receptor gene polymorphisms and serum vascular endothelial growth factor levels in patients with toluene diisocyanate-induced asthma. Clin Exp Allergy 36: 1153–1160CrossRefPubMedGoogle Scholar
  21. 21.
    Kim SH, Cho BY, Park CS, Shin ES, Cho EY, Yang EM, Kim CW, Hong CS, Lee JE, Park HS (2008) Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis. Clin Exp Allergy 39: 203–12CrossRefGoogle Scholar
  22. 22.
    Jeal H, Draper A, Jones M, Harris J, Welsh K, Taylor AN, Cullinan P (2003) HLA associations with occupational sensitization to rat lipocalin allergens: A model for other animal allergies? J Allergy Clin Immunol 111: 795–799CrossRefPubMedGoogle Scholar
  23. 23.
    Smit LA, Bongers SI, Ruven HJ, Rijkers GT, Wouters IM, Heederik D, Omland O, Sigsgaard T (2007) Atopy and new-onset asthma in young Danish farmers and CD14, TLR2, and TLR4 genetic polymorphisms: A nested case-control study. Clin Exp Allergy 37: 1602–1608CrossRefPubMedGoogle Scholar
  24. 24.
    Jones MG, Nielsen J, Welch J, Harris J, Welinder H, Bensryd I, Skerfving S, Welsh K, Venables KM, Taylor AN (2004) Association of HLA-DQ5 and HLA-DR1 with sensitization to organic acid anhydrides. Clin Exp Allergy 34: 812–816CrossRefPubMedGoogle Scholar
  25. 25.
    Nielsen J, Johnson U, Welinder H, Bensryd I, Rylander L, Skerfving S (1996) HLA and immune nonresponsiveness in workers exposed to organic acid anhydrides. J Occup Environ Med 38: 1087–1090CrossRefPubMedGoogle Scholar
  26. 26.
    Young RP, Barker RD, Pile KD, Cookson WO, Taylor AJ (1995) The association of HLA-DR3 with specific IgE to inhaled acid anhydrides. Am J Respir Crit Care Med 151: 219–221PubMedGoogle Scholar
  27. 27.
    Newman Taylor AJ, Cullinan P, Lympany PA, Harris JM, Dowdeswell RJ, du Bois RM (1999) Interaction of HLA phenotype and exposure intensity in sensitization to complex platinum salts. Am J Respir Crit Care Med 160: 435–438PubMedGoogle Scholar
  28. 28.
    Horne C, Quintana PJ, Keown PA, Dimich-Ward H, Chan-Yeung M (2000) Distribution of DRB1 and DQB1 HLA class II alleles in occupational asthma due to western red cedar. Eur Respir J 15: 911–914CrossRefPubMedGoogle Scholar
  29. 29.
    Sjostedt L, Willers S, Orbaek P (1996) Human leukocyte antigens in occupational allergy: A possible protective effect of HLA-B16 in laboratory animal allergy. Am J Ind Med 30: 415–420CrossRefPubMedGoogle Scholar
  30. 30.
    Arnaiz NO, Kaufman JD, Daroowalla FM, Quigley S, Farin F, Checkoway H (2003) Genetic factors and asthma in aluminum smelter workers. Arch Environ Health 58: 197–200CrossRefPubMedGoogle Scholar
  31. 31.
    Mackay IR, Oliphant RC, Laby B, Smith MM, Fisher JN, Mitchell RJ, Propert DN, Tait BD (1990) An immunologic and genetic study of asthma in workers in an aluminum smelter. J Occup Med 32: 1022–1026PubMedGoogle Scholar
  32. 32.
    Hoover RN (2007) The evolution of epidemiologic research: From cottage industry to “big” science. Epidemiology 18: 13–17CrossRefPubMedGoogle Scholar
  33. 33.
    Kauffmann F, Nadif R (2007) Candidate interactions. Eur Respir J 30: 3–4CrossRefPubMedGoogle Scholar
  34. 34.
    Willis-Owen SA, Valdar W (2009). Deciphering gene-environment interactions through mouse models of allergic asthma. J Allergy Clin Immunol 123: 14–23CrossRefPubMedGoogle Scholar
  35. 35.
    Brooks SM (2008) Irritant-induced chronic cough: Irritant-induced TRPpathy. Lung 186 (Suppl 1): S88–93CrossRefGoogle Scholar
  36. 36.
    Blanc P, Liu D, Juarez C, Boushey HA (1991) Cough in hot pepper workers. Chest 99: 27–32CrossRefPubMedGoogle Scholar
  37. 37.
    Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14 000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661–678CrossRefGoogle Scholar
  38. 38.
    Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, Depner M, von Berg A, Bufe A, Rietschel E et al (2007) Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448: 470–473CrossRefPubMedGoogle Scholar
  39. 39.
    Bouzigon E, Corda E, Aschard H, Dizier MH, Boland A, Bousquet J, Chateigner N, Gormand F, Just J, Le Moual N et al (2008) Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med 359: 1985–1994CrossRefPubMedGoogle Scholar
  40. 40.
    Tharrault H, Le Moual N, Aschard H, Bouzigon E, Vervloet D, Siroux V, Dizier MH, Oryszczyn MP, Nadif R, Pin I et al (2008) Associations of asthma with 1270 SNPs from the MHC region and potential interactions with occupational asthmagens in adults from the EGEA study. Am J Respir Crit Care Med 177: A335Google Scholar
  41. 41.
    Horton R, Wilming L, Rand V, Lovering RC, Bruford EA, Khodiyar VK, Lush MJ, Povey S, Talbot CC Jr, Wright MW et al (2004) Gene map of the extended human MHC. Nat Rev Genet 5: 889–899CrossRefPubMedGoogle Scholar
  42. 42.
    Bush WS, Dudek SM, Ritchie MD (2006) Parallel multifactor dimensionality reduction: A tool for the large-scale analysis of gene-gene interactions. Bioinformatics 22: 2173–2174CrossRefPubMedGoogle Scholar
  43. 43.
    Motsinger-Reif AA, Dudek SM, Hahn LW, Ritchie MD (2008) Comparison of approaches for machine-learning optimization of neural networks for detecting genegene interactions in genetic epidemiology. Genet Epidemiol 32: 325–340CrossRefPubMedGoogle Scholar
  44. 44.
    Gibson G (2009). Decanalization and the origin of complex disease. Nat Rev Genet 10: 134–140CrossRefPubMedGoogle Scholar
  45. 45.
    Wong MY, Day NE, Luan JA, Chan KP, Wareham NJ (2003) The detection of geneenvironment interaction for continuous traits: Should we deal with measurement error by bigger studies or better measurement? Int J Epidemiol 32: 51–57CrossRefPubMedGoogle Scholar
  46. 46.
    Wild CP (2005) Complementing the genome with an “exposome”: The outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol Biomarkers Prev 14: 1847–1850CrossRefPubMedGoogle Scholar
  47. 47.
    Pepe MS, Janes H, Longton G, Leisenring W, Newcomb P (2004) Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker. Am J Epidemiol 159: 882–890CrossRefPubMedGoogle Scholar
  48. 48.
    Beghe B, Padoan M, Moss CT, Barton SJ, Holloway JW, Holgate ST, Howell WM, Mapp CE (2004) Lack of association of HLA class I genes and TNF alpha-308 polymorphism in toluene diisocyanate-induced asthma. Allergy 59: 61–64CrossRefPubMedGoogle Scholar
  49. 49.
    Castro-Giner F, Kauffmann F, de Cid R, Kogevinas M (2006) Gene-environment interactions in asthma. Occup Environ Med 63: 776–786, 761CrossRefPubMedGoogle Scholar
  50. 50.
    Pacheco K, Maier L, Silveira L, Goelz K, Noteware K, Luna B, du Bois R, Murphy J, Rose C (2008) Association of Toll-like receptor 4 alleles with symptoms and sensitization to laboratory animals. J Allergy Clin Immunol 122: 896–902 e894CrossRefPubMedGoogle Scholar

Copyright information

© Birkhäuser / Springer Basel 2010

Authors and Affiliations

  • Francine Kauffmann
    • 1
    • 2
  • Francesc Castro-Giner
    • 3
    • 4
    • 5
  • Lidwien A. M. Smit
    • 1
    • 2
  • Rachel Nadif
    • 1
    • 2
  • Manolis Kogevinas
    • 3
    • 4
    • 5
    • 6
  1. 1.InsermU780 — Epidemiology and BiostatisticsVillejuifFrance
  2. 2.Université Paris SudVillejuifFrance
  3. 3.Center for Research in Environmental Epidemiology (CREAL)BarcelonaSpain
  4. 4.Municipal Institute of Medical ResearchBarcelonaSpain
  5. 5.CIBER Epidemiologia y Salud Publica (CIBERESP)Spain
  6. 6.Medical SchoolUniversity of CreteHeraklionGreece

Personalised recommendations