Index > Vol. 88/2008 > Iss. 1/January > pp. 15-19 > Abstract
Investigative Report | Atopy, Atopy, Inherited diseases and malformations

Loss-of-function Variants of the Filaggrin Gene are Associated with Atopic Eczema and Associated Phenotypes in Swedish Families

doi: 10.2340/00015555-0383

Abstract:

Recent studies have identified 2 loss-of-function variants, R501X and 2282del4, in the filaggrin gene as predisposing factors in the development of eczema. In this study, representing the first analysis of the variants in a Swedish population, we analysed transmission in 406 multiplex eczema families with mainly adult patients. In accordance with previous studies we found association between the filaggrin gene variants and atopic eczema (p = 9.5×10–8). The highest odds ratio for the combined allele, 4.73 (1.98–11.29), p = 3.6×10–8, was found for the subgroup with a severe eczema phenotype, and association was also found with raised allergen-specific IgE, allergic asthma and allergic rhinoconjunctivitis occurring in the context of eczema. Our results support an important role for the filaggrin gene variants R501X and 2282del4 in the development and severity of atopic eczema and indicate a possible role for the subsequent progression into eczema-associated phenotypes.

Authors:

Elisabeth Ekelund, Agne Liedén, Jenny Link, Simon P. Lee, Mauro D'Amato, Colin N.A. Palmer, Ingrid Kockum, Maria Bradley

Key words:

eczema; atopic dermatitis; genetic association; filaggrin; R501X; 2282del4.

References

  1. Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol 2004; 113: 832–836.
  2. Morar N, Willis-Owen SAG, Moffatt MF, Cookson WOCM. The genetics of atopic dermatitis. J Allergy Clin Immunol 2006; 118: 24–34.
  3. Flohr C, Johansson SG, Wahlgren CF, Williams H. How atopic is atopic dermatitis? J Allergy Clin Immunol 2004; 114: 150–158.
  4. Larsen FS, Holm NV, Henningsen K. Atopic dermatitis. A genetic-epidemiologic study in a population-based twin sample. J Am Acad Dermatol 1986; 15: 487–494.
  5. Schultz Larsen F. Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J Am Acad Dermatol 1993; 28: 719–723.
  6. Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, 
Moustafa M, MacGowan A, et al. New perspectives on epidermal barrier dysfunction in atopic dermatitis: Gene-environment interactions. J Allergy Clin Immunol 2006; 118: 3–21.
  7. Cookson WOCM, Ubhi B, Lawrence R, Abecasis GR, 
Walley AJ, Cox HE, et al. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat Genet 2001; 27: 372–373. Link to article
  8. 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: 337–342. Link to article
  9. 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 atopic dermatitis. Nat Genet 2006; 38: 441–446. Link to article
  10. Dale BA, Resing KA, Lonsdale-Eccles JD. Filaggrin: a keratin filament associated protein. Ann N Y Acad Sci 1985; 455: 330–342. Link to article
  11. Gan SQ, McBride OW, Idler WW, Markova N, Steinert PM. Organization, structure, and polymorphisms of the human profilaggrin gene. Biochemistry 1990; 29: 9432–9440. Link to article
  12. Steinert PM, Cantieri JS, Teller DC, Lonsdale-Eccles JD, Dale BA. Characterization of a class of cationic proteins that specifically interact with intermediate filaments. Proc Natl Acad Sci USA 1981; 78: 4097–4101. Link to article
  13. Bradley M, Kockum I, Soderhall C, Van Hage-Hamsten M, Luthman H, Nordenskjold M, et al. Characterization by phenotype of families with atopic dermatitis. Acta Derm Venereol 2000; 80: 106–110.
  14. Bradley M, Soderhall C, Luthman H, Wahlgren CF, Kockum I, Nordenskjold M. Susceptibility loci for atopic dermatitis on chromosomes 3, 13, 15, 17 and 18 in a Swedish population. Human Mol Genet 2002; 11: 1539–1548. Link to article
  15. Williams HC, Burney PG, Hay RJ, Archer CB, Shipley MJ, Hunter JJ, et al. The U. Working Party’s Diagnostic Criteria for Atopic Dermatitis. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol 1994; 131: 383–396. Link to article
  16. Sandilands A, Terron-Kwiatkowski A, Hull PR, O’Regan G M, Clayton TH, Watson RM, et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet 2007; 39: 650–654. Link to article
  17. Martin ER, Monks SA, Warren LL, Kaplan NL. A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 2000; 67: 146–154. Link to article
  18. Dudbridge F. Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121. Link to article
  19. Irvine AD. Fleshing out filaggrin phenotypes. J Invest Dermatol 2007; 127: 504–507. Link to article
  20. Nomura T, Sandilands A, Akiyama M, Liao H, Evans AT, Sakai K, et al. Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol 2007; 119: 434–440.
  21. Marenholz I, Nickel R, Ruschendorf 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: 866–871.
  22. 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 atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol 2006; 118: 214–219.
  23. Ruether A, Stoll M, Schwarz T, Schreiber S, Fölster-Holst R. Filaggrin loss-of-function variant contributes to atopic dermatitis risk in the population of Northern Germany. Br J Dermatol 2006; 155: 1093–1094.
  24. Morar N, Cookson WO, Harper JI, Moffatt MF. Filaggrin mutations in children with severe atopic dermatitis. J Invest Dermatol 2007; 127: 1667–1672.
  25. Weidinger S, Rodriguez E, Stahl C, Wagenpfeil S, Klopp N, Illig T, et al. Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. J Invest Dermatol 2007; 127: 724–726. Link to article
  26. Barker JN, Palmer CN, Zhao Y, Liao H, Hull PR, Lee SP, 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. Link to article