Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2017, vol. 26, nr 6, September, p. 991–998

doi: 10.17219/acem/61430

Publication type: original article

Language: English

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Filaggrin loss-of-function mutations as a predictor for atopic eczema, allergic sensitization and eczema-associated asthma in Polish children population

Anna Dębińska1,A,B,C,D,E, Hanna Danielewicz1,A,B,C,E, Anna Drabik-Chamerska1,B,C, Danuta Kalita1,B,C, Andrzej Boznański1,A,E,F

1 1st Department and Clinic of Pediatrics, Allergology and Cardiology, Wroclaw Medical University, Poland

Abstract

Background. Loss-of-function mutations in the filaggrin (FLG) gene were identified as a major risk factor for atopic eczema.
Objectives. The aim of the study was to investigate the importance of 4 common FLG null mutations in the susceptibility to atopic eczema and other allergic phenotypes in Polish children population.
Material and Methods. The FLG mutations were determined in 158 children younger than 2 years of age. All subjects were selected using a detailed questionnaire and blood samples for total and specific IgE measurements were obtained. Cases of atopic eczema were diagnosed according to the criteria of Hanifin and Rajka and skin examination. All FLG mutations were genotyped by real-time PCR assays with a subsequent melting curve analysis using a SimpleProbe® probes.
Results. The combined genotype of all 4 mutations (carriage of ≥ 1 FLG mutation) was significantly associated with atopic eczema (p = 0.016). The odds ratio (OR) for individuals carrying 1 of these 4 null mutations was 5.52 (95% CI; 1.11 ÷ 37.12). The significant association between either the combined FLG genotype or 2282del14 deletion and eczema was seen only in the allergic group. The association with asthma was restricted to asthma occurring in the context of eczema (OR, 6.27; 95% CI, 0.89 ÷ 53.56; p = 0.042).
Conclusion. Our study confirms the previous findings that FLG mutations are strongly associated with atopic eczema and confer a significant risk of allergic sensitization and asthma in the context of eczema. These results underline the role of the epidermal barrier and filaggrin insufficiency in the pathogenesis of atopic eczema and eczema-associated asthma.

Key words

asthma, atopic dermatitis, atopic eczema, genotype, mutation

References (31)

  1. Schultz Larsen F, Hanifin J. Epidemiology of atopic dermatitis. Immunol Allergy Clin North Am. 2002;22:1–24.
  2. Cork MJ, Robinson DA, Vasilopoulos Y, et al. New perspectives on epidermal barrier dysfunction in atopic dermatitis: Gene–environment interactions. J Allergy Clin Immunol. 2006;118:3–21.
  3. Palmer CNA, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38:441–446.
  4. Brown SJ, McLean WH. One remarkable molecule: Filaggrin. J Invest Dermatol. 2012;132:650–654.
  5. McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol. 2013;131:280–291.
  6. Cookson WO, Ubhi B, Lawrence R, et al. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat Genet. 2001;27:372–373.
  7. Mildner M, Jin J, Eckhart L, et al. Knockdown of filaggrin impairs diffusion barrier function and increases UV sensitivity in a human skin model. J In­vest Dermatol. 2010;130:2286–2294.
  8. 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.
  9. Rodriguez E, Baurecht H, Herberich E, et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: Robust risk factors in atopic dermatitis. J Allergy Clin Immunol. 2009;123:1361–1370.
  10. Marenholz I, Nickel R, Ruschendorf F, et al. Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic March. J Allergy Clin Immunol. 2006;118:866–871.
  11. Marenholz I, Kerscher T, Bauerfeind A, et al. An interaction between filaggrin mutations and early food sensitization improves the prediction oh childhood asthma. J Allergy Clin Immunol. 2009;123:911–916.
  12. Henderson J, Northstone K, Lee SP, et al. The burden of disease associated with filaggrin mutations: A population-based, longitudinal birth cohort study. J Allergy Clin Immunol. 2008;121:872–877.
  13. Weidinger S, O'Sullivan M, Illig T, et al. Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J Allergy Clin Immunol. 2008;121:1203–1209
  14. Hanifin JM, Rajka G. Diagnostic featrures of atopic dermatitis. Acta Derm Venerol Suppl (Stockh). 1980;92:44–47.
  15. Lesiak A, Przybyłowska K, Zakrzewski M, et al. Mutacje R501X i 2282del14 w genie filagryny a atopowe zapalenie skóry. Alergia Astma Immunologia. 2010;15:162–169.
  16. Ponińska J, Samoliński B, Tomaszewska 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.
  17. Presland RB, Boggess D, Lewis SP, Hull C, Flackman P, Sundberg JP. Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice: An animal model for the filaggrin-deficient skin disease ichthyosis vulgaris. J Invest Dermatol. 2000;115:1072–1081.
  18. Sandilands A, Terron-Kwiatkowski A, Hull PR, et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutation in ichthyosis vulgaris and atopic eczema. Nat Genet. 2007;39:650–654.
  19. Giardina E, Paolillo N, Sinibaldi C, et al. R501X and 2282del4 filaggrin mutations do not confer susceptibility to psoriasis and atopic dermatitis in Italian patients. Dermatology. 2008;216:83–84.
  20. Ercan H, Ispir T, Kirac D, et al. Predictors of atopic dermatitis phenotypes and severity: Role of serum immunoglobulins and filaggrin gene mutations R501X. Allergol Immunopathol. 2013;41:86–93.
  21. Weidinger S, Rodriguez E, Stahl C, et al. Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. J Invest Dermatol. 2007;127:724–726.
  22. Barker JN, Palmer CN, Zhao Y, et al. Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood. J Invest Dermatol. 2007;127:564–567.
  23. Stemmler S, Parwez Q, Petrasch-Parwez E, Epplen JT, Hoffjan S. Two common loss-of-function mutations within the filaggrin gene predispose for early onset of atopic dermatitis. J Invest Dermatol. 2007;127:722–724.
  24. Ho-Sung Y, Mi-Jin K, Young-Ho J, et al. Mutations at filaggrin are predisposing factor in Korean children with atopic dermatitis. Allergy Asthma Immunol Res. 2013;5:211–215.
  25. Zhang H, Guo Y, Wang W, Shi M, Chen X, Yao Z. Mutations in the filaggrin gene in Han Chinese patients with atopic dermatitis. Allergy. 2011;66:420–427.
  26. Bořnnelykke K, Pipper CB, Tavendale R, Palmer CNA, Bisgaard H. Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth. Pediatr Allergy Immunol. 2010;21:954–961.
  27. Fallon PG, Sasaki T, Sandilands A, et al. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet. 2009;41:602–608.
  28. De Benedetto A, Kubo A, Beck LA. Skin barrier disruption: A requirement for allergen sensitization? J Invest Dermatol. 2008;132:949–963.
  29. Ying S, Meng Q, Corrigan CJ, Lee TH. Lack of filaggrin expression in the human bronchial mucosa. J Allergy Clin Immunol. 2006;118:1386–1388.
  30. He R, Oyoshi MK, Jin H, Geha RS. Epicutaneous antigen exposure induces a Th17 response that drives airway inflammation after inhalation challenge. Proc Natl Acad Sci. 2007;104:15817–15822.
  31. Bisgaard H, Bonnelykke K. Long-term studies of the natural history of asthma in childhood. J Allergy Clin Immunol. 2010;126:187–119.
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