Filaggrin pp 169-181 | Cite as

Asthma

Chapter
First Online:

Abstract

Asthma is a common chronic inflammatory disease of the airways characterized by wheezing, shortness of breath, chest tightness, and cough. Asthma is closely associated with atopic dermatitis (AD), and individuals with AD have a marked increased risk of later asthma. Interestingly, this increased risk is probably dose dependent so that individuals with early onset AD or more severe eczema have an even higher risk of later development of asthma. The advent of loss-of-function mutations in the filaggrin gene (FLG) has led to the hypothesis that the skin acts as the site of primary allergic sensitization through defects in the epidermal barrier with secondary reactivity in the airways. Several studies of independent populations chiefly from Europe, the United States, and Asia have shown that the overall risk of asthma in FLG mutation carriers is increased about 1.5 times relative to noncarriers. In contrast, the risk of asthma in individuals with AD carrying FLG null mutations appears to be increased about three times relative to noncarriers, whereas their risk of eczema-free asthma seems not to be increased. Besides affecting the risk of asthma in patients with AD, FLG mutation carriers also seem to have more severe asthma and an increased risk of asthma exacerbations.

Keywords

Atopic Dermatitis Alopecia Areata Atopic Dermatitis Patient Combine Genotype Netherton Syndrome 
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.
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Asher MI, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland SK, Williams H. ISAAC Phase Three Study Group. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368:733–43.PubMedCrossRefGoogle Scholar
  2. 2.
    Nolte H, Nepper-Christensen S, Backer V. Unawareness and undertreatment of asthma and allergic rhinitis in a general population. Respir Med. 2006;100:354–62.PubMedCrossRefGoogle Scholar
  3. 3.
    Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299:1259–60.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Thyssen JP, Linneberg A, Johansen JD, Carlsen BC, Zachariae C, Meldgaard M, et al. Atopic diseases by filaggrin mutations and birth year. Allergy. 2012;67:705–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Lougheed MD, Turcotte SE, Fisher T. Cough variant asthma: lessons learned from deep inspirations. Lung. 2012;190:17–22.PubMedCrossRefGoogle Scholar
  6. 6.
    Global Initiative for Asthma. www.ginasthma.org.
  7. 7.
    Agache I, Akdis C, Jutel M, Virchow JC. Untangling asthma phenotypes and endotypes. Allergy. 2012;67:835–46.PubMedCrossRefGoogle Scholar
  8. 8.
    Rackeman FM. A working classification of asthma. Am J Med. 1947;3:601–6.CrossRefGoogle Scholar
  9. 9.
    Lugogo NL, Kraft M, Dixon AE. Does obesity produce a distinct asthma phenotype? J Appl Physiol. 2010;108:729–34.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2008;8:183–92.PubMedCrossRefGoogle Scholar
  11. 11.
    Thomsen SF, van der Sluis S, Kyvik KO, Skytthe A, Backer V. Estimates of asthma heritability in a large twin sample. Clin Exp Allergy. 2010;40:1054–61.PubMedCrossRefGoogle Scholar
  12. 12.
    Vercelli D. Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol. 2008;8:169–82.PubMedCrossRefGoogle Scholar
  13. 13.
    Gibson G. Decanalization and the origin of complex disease. Nat Rev Genet. 2009;10:134–40.PubMedCrossRefGoogle Scholar
  14. 14.
    Spergel JM. From AD, to asthma: the atopic march. Ann Allergy Asthma Immunol. 2010;105:99–106.PubMedCrossRefGoogle Scholar
  15. 15.
    Lowe AJ, Carlin JB, Bennett CM, Hosking CS, Abramson MJ, Hill DJ, Dharmage SC. Do boys do the atopic march while girls dawdle? J Allergy Clin Immunol. 2008;121:1190–5.PubMedCrossRefGoogle Scholar
  16. 16.
    De Benedetto A, Kubo A, Beck LA. Skin barrier disruption: a requirement for allergen sensitization? J Invest Dermatol. 2012;132:949–63.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Kubo A, Nagao K, Amagai M. Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases. J Clin Invest. 2012;122:440–7.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011;365:1315–27.PubMedCrossRefGoogle Scholar
  19. 19.
    van den Oord RA, Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. BMJ. 2009;339:b2433.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Rodriguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown SJ, Cordell HJ, et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J Allergy Clin Immunol. 2009;123:1361–70.PubMedCrossRefGoogle Scholar
  21. 21.
    Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for AD. Nat Genet. 2006;38:441–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Marenholz I, Nickel R, Rüschendorf F, Schulz F, Esparza-Gordillo J, Kerscher T, et al. Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J Allergy Clin Immunol. 2006;118:866–71.PubMedCrossRefGoogle Scholar
  23. 23.
    Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, et al. Loss-of-function variations within the filaggrin gene predispose for AD with allergic sensitizations. J Allergy Clin Immunol. 2006;118:214–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Weidinger S, Rodríguez E, Stahl C, Wagenpfeil S, Klopp N, Illig T, et al. Filaggrin mutations strongly predispose to early onset and extrinsic AD. J Invest Dermatol. 2007;127:724–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Morar N, Cookson WO, Harper JI, Moffatt MF. Filaggrin mutations in children with severe AD. J Invest Dermatol. 2007;127:1667–72.PubMedGoogle Scholar
  26. 26.
    Rogers AJ, Celedón JC, Lasky-Su JA, Weiss ST, Raby BA. Filaggrin mutations confer susceptibility to AD but not to asthma. J Allergy Clin Immunol. 2007;120:1332–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Hubiche T, Ged C, Benard A, Léauté-Labrèze C, McElreavey K, de Verneuil H, et al. Analysis of SPINK 5, KLK 7 and FLG genotypes in a French AD cohort. Acta Derm Venereol. 2007;87:499–505.PubMedCrossRefGoogle Scholar
  28. 28.
    Ekelund E, Liedén A, Link J, Lee SP, D’Amato M, Palmer CN, et al. Loss-of-function variants of the filaggrin gene are associated with atopic eczema and associated phenotypes in Swedish families. Acta Derm Venereol. 2008;88:15–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Müller S, Marenholz I, Lee YA, Sengler C, Zitnik SE, Griffioen RW, et al. Association of Filaggrin loss-of-function-mutations with AD and asthma in the Early Treatment of the Atopic Child (ETAC) population. Pediatr Allergy Immunol. 2009;20:358–61.PubMedCrossRefGoogle Scholar
  30. 30.
    Greisenegger E, Novak N, Maintz L, Bieber T, Zimprich F, Haubenberger D, et al. Analysis of four prevalent filaggrin mutations (R501X, 2282del4, R2447X and S3247X) in Austrian and German patients with AD. J Eur Acad Dermatol Venereol. 2010;24:607–10.PubMedCrossRefGoogle Scholar
  31. 31.
    Lesiak A, Kuna P, Zakrzewski M, van Geel M, Bladergroen RS, Przybylowska K, et al. Combined occurrence of filaggrin mutations and IL-10 or IL-13 polymorphisms predisposes to AD. Exp Dermatol. 2011;20:491–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Li M, Chen X, Chen R, Bao Y, Yao Z. Filaggrin gene mutations are associated with independent atopic asthma in Chinese patients. Allergy. 2011;66:1616–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Osawa R, Konno S, Akiyama M, Nemoto-Hasebe I, Nomura T, Nomura Y, et al. Japanese-specific filaggrin gene mutations in Japanese patients suffering from atopic eczema and asthma. J Invest Dermatol. 2010;130:2834–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Wang IJ, Lin TJ, Kuo CF, Lin SL, Lee YL, Chen PC. Filaggrin polymorphism P478S, IgE level, and atopic phenotypes. Br J Dermatol. 2011;164:791–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Zhang H, Guo Y, Wang W, Shi M, Chen X, Yao Z. Mutations in the filaggrin gene in Han Chinese patients with AD. Allergy. 2011;66:420–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Brown SJ, Relton CL, Liao H, Zhao Y, Sandilands A, Wilson IJ, et al. Filaggrin null mutations and childhood atopic eczema: a population-based case-control study. J Allergy Clin Immunol. 2008;121:940–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Henderson J, Northstone K, Lee SP, Liao H, Zhao Y, Pembrey M, et al. The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study. J Allergy Clin Immunol. 2008;121:872–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Rice NE, Patel BD, Lang IA, Kumari M, Frayling TM, Murray A, et al. Filaggrin gene mutations are associated with asthma and eczema in later life. J Allergy Clin Immunol. 2008;122:834–6.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Weidinger S, O’Sullivan M, Illig T, Baurecht H, Depner M, Rodriguez E, et al. Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J Allergy Clin Immunol. 2008;121:1203–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Schuttelaar ML, Kerkhof M, Jonkman MF, Koppelman GH, Brunekreef B, de Jongste JC, et al. Filaggrin mutations in the onset of eczema, sensitization, asthma, hay fever and the interaction with cat exposure. Allergy. 2009;64:1758–65.PubMedCrossRefGoogle Scholar
  41. 41.
    Poninska J, Samolinski B, Tomaszewska A, Raciborski F, Samel-Kowalik P, Walkiewicz A, et al. Filaggrin gene defects are independent risk factors for atopic asthma in a Polish population: a study in ECAP cohort. PLoS One. 2011;6:e16933.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Marenholz I, Bauerfeind A, Esparza-Gordillo J, Kerscher T, Granell R, Nickel R, et al. The eczema risk variant on chromosome 11q13 (rs7927894) in the population-based ALSPAC cohort: a novel susceptibility factor for asthma and hay fever. Hum Mol Genet. 2011;20:2443–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Berg ND, Husemoen LL, Thuesen BH, Hersoug LG, Elberling J, Thyssen JP, et al. Interaction between filaggrin null mutations and tobacco smoking in relation to asthma. J Allergy Clin Immunol. 2012;129:374–80.PubMedCrossRefGoogle Scholar
  44. 44.
    Sabolic Pipinic I, Varnai VM, Turk R, Breljak D, Kezic S, Macan J. Low frequency of filaggrin null mutations in Croatia and their relation with allergic diseases. Int J Immunogenet. 2013;40:192–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006;38:337–42.PubMedCrossRefGoogle Scholar
  46. 46.
    Sandilands A, Terron-Kwiatkowski A, Hull PR, O’Regan GM, Clayton TH, Watson RM, Carrick T, et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet. 2007;39:650–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Bisgaard H, Simpson A, Palmer CN, Bønnelykke K, McLean I, Mukhopadhyay S, et al. Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure. PLoS Med. 2008;5:e131.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Marenholz I, Kerscher T, Bauerfeind A, Esparza-Gordillo J, Nickel R, Keil T, et al. An interaction between filaggrin mutations and early food sensitization improves the prediction of childhood asthma. J Allergy Clin Immunol. 2009;123:911–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Palmer CN, Ismail T, Lee SP, Terron-Kwiatkowski A, Zhao Y, Liao H, et al. Filaggrin null mutations are associated with increased asthma severity in children and young adults. J Allergy Clin Immunol. 2007;120:64–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Basu K, Palmer CN, Lipworth BJ, Irwin McLean WH, Terron-Kwiatkowski A, Zhao Y, et al. Filaggrin null mutations are associated with increased asthma exacerbations in children and young adults. Allergy. 2008;63:1211–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Bønnelykke K, Pipper CB, Tavendale R, Palmer CN, Bisgaard H. Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth. Pediatr Allergy Immunol. 2010;21:954–61.PubMedCrossRefGoogle Scholar
  52. 52.
    Betz RC, Pforr J, Flaquer A, Redler S, Hanneken S, Eigelshoven S, et al. Loss-of-function mutations in the filaggrin gene and alopecia areata: strong risk factor for a severe course of disease in patients comorbid for atopic disease. J Invest Dermatol. 2007;127:2539–43.PubMedCrossRefGoogle Scholar
  53. 53.
    Van Limbergen J, Russell RK, Nimmo ER, Zhao Y, Liao H, Drummond HE, et al. Filaggrin loss-of-function variants are associated with atopic comorbidity in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2009;15:1492–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Landeck L, Visser M, Kezic S, John SM. Genotype-phenotype associations in filaggrin loss-of-function mutation carriers. Contact Dermatitis. 2013;68:149–55.PubMedCrossRefGoogle Scholar
  55. 55.
    Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet. 2000;25:141–2.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of DermatologyBispebjerg HospitalCopenhagenDenmark

Personalised recommendations