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Research Updates

W H Irwin McLean, PhD, DSc, FRSE

A Recent Advance in Our Genetic Understanding of Atopic Dermatitis (AD)

Irwin McLean

Tuesday, March 06, 2007

Atopic dermatitis (AD), or eczema, is one of the biggest challenges within the field of dermatology both in the clinic and in the research laboratory.1 The condition, along with associated allergy, asthma, and rhinitis, has increased in incidence in recent decades and now affects 15-20% of children in the developed world and therefore represents a huge global healthcare burden. AD is a classic multifactorial trait where genetic predisposition factors act in conjunction with environmental influences to produce disease. Since there is inflammation of the epidermis in AD, there is a strong immunological component in the course of the disease; however, a defect in skin barrier function has long been suspected as the primary cause.

Early in 2006, a definitive epidermal barrier defect was identified in AD when my research group in Scotland, with collaborators in Ireland, Denmark, and the United States, identified mutations in the FLG gene that encodes filaggrin. First, we unambiguously showed that these mutations are the cause of ichthyosis vulgaris (IV) - a very common monogenic trait characterized by dry, flaky skin, particularly in cold weather and/or dry climates.2 To our surprise, we found that two null mutations in FLG, R501X and 2282del4 are carried by 9-10% of people in Ireland and Scotland, and are present at similar levels in other European-origin populations. As many people with IV also have AD and, furthermore, FLG resides in a known AD susceptibility locus on chromosome 1q21,3 we examined the role of these mutations in AD and found extremely statistically significant associations.4 We replicated the association in the Scottish, Irish, and Danish populations by a variety of genetic methods (linkage analysis, case:control association study, prospective study). The role of FLG mutations in AD has since been independently confirmed in a number of studies of different European populations by a variety of case:control association and genetic transmission methodologies.5-10 In all cases, FLG null alleles were found to be a major genetic factor and, in most of the studies, the genetic association was highly statistically significant for each of the two common filaggrin null mutations alone, giving within-study replication. Importantly, and in contrast to other genetic studies in AD, there have been no negative studies in the European population where these particular mutations are relevant.

Both of the common FLG mutations lead to complete loss of filaggrin production in the epidermis, as shown by biochemical analysis.2 The keratohyalin granules in the outer epidermis are predominantly composed of the giant polyprotein profilaggrin.11 Upon terminal differentiation of keratinocytes in the uppermost granular layer for form squames, profilaggrin is proteolytically cleaved into multiple copies of the filaggrin peptide. This molecule binds to and aggregates the keratin cytoskeleton within these cells, which helps bring about cell compaction into squames. This condensed protein-lipid package is chemically cross-linked and forms the basis of the skin barrier function that resides in the stratum corneum. Thus, filaggrin is a key player in formation of the stratum corneum and skin barrier formation. A secondary function for filaggrin has been suggested, where it may be further broken down within the stratum corneum into hygroscopic amino acids and/or derivatives thereof, which may contribute to a inherent moisturizing or humectant activity.12 People who carry one of the FLG null mutations, about 10% of white European people, make only 50% of the normal levels of filaggrin. They may have mild features of IV and are genetically predisposed to development of AD. About 1 in 400 inherit two filaggrin null alleles and make no filaggrin whatsoever in their skin. They have a severe presentation of IV and are more strongly predisposed to AD.

Recently, we have identified a further loss-of-function mutation in FLG, 3702delG, that also contributes to both IV and AD and it is likely that a range of mutations will emerge in the near future.8 Like 3702delG, some of these variants may be rare in the population, whereas others, like R501X or 2282del4, may be more prevalent. Furthermore, it is likely that other non-European ethnic groups will have their own spectrum of FLG mutations causing IV and contributing to AD. FLG is a highly repetitive gene that is difficult to fully sequence on a routine basis and therefore it will take some time before its global contribution to AD fully comes to light.13 Certainly, IV is common in most or all human populations and this appears to be a fairly unambiguous marker for a filaggrin mutation. AD is very common worldwide and it is possible that other populations carry their own spectrum of prevalent mutations so that FLG might be an important AD susceptibility gene in a global sense. However, it may be that other genes that contribute to epidermal barrier formation might be more important in some populations. Some of these barrier genes may relate to filaggrin in some way.

Overall, the FLG studies point to a pivotal role for molecular and cellular events relating to the terminal stages of epidermal differentiation in the pathogenesis of AD. Although more research is required to elucidate the mechanism of action of these genetic variants in AD, it seems plausible that an impaired skin barrier function exposes the immune system to antigens, allergens, and chemicals that it normally does not come into contact with. If the immune system reacts strongly to this enhanced cutaneous sensitization, it results in AD and associated allergic conditions.14 The other diseases that contribute to the "atopic march," typically eczema-associated asthma, rhinitis, and other allergies, are certainly strongly associated with FLG mutations.4,6,10 Obviously, there are inter-individual variations in the genetic basis of the immune system as well as differences in people's antigenic environment, which may explain why not everyone with a FLG mutation will develop AD, although these alleles are in fact highly penetrant.

This work has many implications for future research. With the discovery of the FLG mutations, the AD field now has a new genetic test that needs to be assessed and deployed within the context of all other genetic, environmental, and pharmacological studies. In the immediate future, large longitudinal studies are important to accurately determine the population-attributable risk for AD and other atopic disease phenotypes due to FLG mutations and to determine the predictive utility of genetic testing. FLG analysis should now be considered in clinical trials of new and existing AD treatments to see if this subset of filaggrin-deficient AD subjects respond differently. Filaggrin status should also be examined in studies of environmental triggers of AD flare-up. It will also now be possible to remove FLG mutation carriers from AD study cohorts and then carry out genetic linkage studies to assess what genetic contribution other non-filaggrin on 1q21 or, other known AD loci, make to the remainder of AD. Finally, in the longer term, it should be possible to develop pharmacological interventions to boost filaggrin or other barrier proteins in the epidermis to either treat or perhaps even prevent the onset of atopic disease.

Now that the barriers to filaggrin gene analysis have been lifted, the coming months and years should see a great deal of exciting activity in skin barrier research within the atopy field.


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  2. Smith FJD, Irvine AD, Terron-Kwiatkowski A, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006 Mar;38(3):337-42.
  3. Cookson WO, Ubhi B, Lawrence R, et al. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat Genet. 2001 Apr;27(4):372-3.
  4. Palmer CN, 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 Apr;38(4):441-6.
  5. 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. 2006 Sep 21; [Epub ahead of print].
  6. 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 Oct;118(4):866-71.
  7. Ruether A, Stoll M, Schwarz T, et al. Filaggrin loss-of-function variant contributes to atopic dermatitis risk in the population of Northern Germany. Br J Dermatol. 2006 Nov;155(5):1093-4.
  8. Sandilands A, O'Regan GM, Liao H, et al. Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis. J Invest Dermatol. 2006 Aug;126(8):1770-5.
  9. Stemmler S, Parwez Q, Petrasch-Parwez E, et al. Two common loss-of-function mutations within the filaggrin gene predispose for early onset of atopic dermatitis. J Invest Dermatol. 2006 Sep 28: [Epub ahead of print].
  10. Weidinger S, Illig T, Baurecht H, et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol. 2006 Jul;118(1):214-9.
  11. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol. 2005 Apr;6(4):328-40.
  12. Rawlings AV, Harding CR. Moisturization and skin barrier function. Dermatol Ther. 2004;17 Suppl 1:43-8.
  13. Irvine AD, McLean WH. Breaking the (un)sound barrier: filaggrin is a major gene for atopic dermatitis. J Invest Dermatol. 2006 Jun;126(6):1200-2.
  14. Hudson TJ. Skin barrier function and allergic risk. Nat Genet. 2006 Apr:38(4):441-6.