Fleshing Out Filaggrin Phenotypes
2007; Elsevier BV; Volume: 127; Issue: 3 Linguagem: Inglês
10.1038/sj.jid.5700695
ISSN1523-1747
Autores Tópico(s)Food Allergy and Anaphylaxis Research
ResumoThe association of filaggrin null alleles with eczema has been replicated in several European populations. Three large, well-conducted studies confirm this association and offer insights into the phenotypic nature of eczema associated with these alleles. Early data suggest that FLG-associated eczema may be more persistent, more likely to have palmar hyperlinearity, and more likely to be associated with asthma. These initial hints will require further confirmation in cohort studies. The association of filaggrin null alleles with eczema has been replicated in several European populations. Three large, well-conducted studies confirm this association and offer insights into the phenotypic nature of eczema associated with these alleles. Early data suggest that FLG-associated eczema may be more persistent, more likely to have palmar hyperlinearity, and more likely to be associated with asthma. These initial hints will require further confirmation in cohort studies. Earlier this year, two recurrent null alleles in filaggrin (FLG) were observed to confer substantial risk of atopic dermatitis (AD; henceforth called eczema, according to the World Allergy Organization nosology (Johansson et al., 2004Johansson S.G. Bieber T. Dahl R. Friedmann P.S. Lanier B.Q. Lockey R.F. 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: 832-836Abstract Full Text Full Text PDF PubMed Scopus (1715) Google Scholar)) and of asthma occurring in the context of eczema (Palmer et al., 2006Palmer C.N. Irvine A.D. Terron-Kwiatkowski A. Zhao Y. Liao H. Lee S.P. 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: 441-446Crossref PubMed Scopus (2088) Google Scholar). Within a short time these two null alleles in FLG (R501X and 2282del4) have become the most widely and independently replicated and most strongly associated genetic factor conferring susceptibility to eczema in European populations to date, with odds ratios of between 3.73 and 7.1 reported in the larger cohorts (Marenholz et al., 2006Marenholz 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: 866-871Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar; Ruether et al., 2006Ruether A. Stoll M. Schwarz T. Schreiber S. Folster-Holst R. Filaggrin loss-of-function variant contributes to atopic dermatitis risk in the population of Northern Germany.BrJ Dermatol. 2006; 155: 1093-1094Crossref PubMed Scopus (83) Google Scholar). In this issue of the Journal of Investigative Dermatology, three additional replication studies are reported (Barker et al., 2007Barker J.N.W.N. Palmer C.N.A. Zhao Y. Liao H. Hull P.R. Lee S.P. 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: 564-567Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar; Stemmler et al., 2007Stemmler S. Parwez Q. Petrasch-Parwez E. Epplen J.T. Hoffjan S. Two common loss-of-function mutations within the filaggrin gene predispose for early onset of atopic dermatitis.J Invest Dermatol. 2007; 127: 722-724Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar; Weidinger et al., 2007Weidinger S. Rodrguez 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: 724-726Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). Each of these studies reports strong association between eczema and FLG null alleles, and each allows further exploration of the genetic contribution of these common recurrent null alleles to the pathogenesis of eczema. A summary of the populations studied to date and relevant findings is presented in Table 1. Significantly, all studies have shown strong replication of association with eczema, and no negative or equivocal study in Europeans, in whom these mutations are prevalent, has been reported. The position of FLG as a major gene in AD is further reinforced by the striking finding that these two common recurrent mutations have a penetrance of 42% in the German Multicenter Allergy Study and that the population attributable risk factor (the proportion of eczema that is directly attributable to these two recurrent null alleles at population level assuming a causal association) for eczema in this cohort was 11% (Marenholz et al., 2006Marenholz 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: 866-871Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar). These calculations of the total cumulative effect of FLG null alleles in eczema are likely to be an underestimate, as several additional recurrent FLG null alleles are present in European populations at lower levels with intra-European, regionally distinct allele frequencies (A. Sandilands, W.H.I. McLean, and A.D. Irvine, unpublished data).Table 1Summary of genetic studies of association of FLG null alleles with eczema and related phenotypesCohort/ethnicityNumber of subjects and characteristics of cohortPhenotype examinedP value (combinedgenotype)Odds ratio% patients with one or more FLG null allelesIrish1(Sandilands et al., 2006Sandilands A. O'Regan G.M. Liao H. Zhao Y. Terron-Kwiatkowski A. Watson R.M. et al.Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis.J Invest Dermatol. 2006; 126: 1770-1775Crossref PubMed Scopus (184) Google Scholar)10 large multiplex families with ichthyosis vulgaris and ADAD and ichthyosis vulgarisLOD 3.96NANAIrish2(Palmer et al., 2006Palmer C.N. Irvine A.D. Terron-Kwiatkowski A. Zhao Y. Liao H. Lee S.P. 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: 441-446Crossref PubMed Scopus (2088) Google Scholar)52 children, early onset, severe ADAD3 × 10−1713.4 (6.2–27.5)56English3(Barker et al., 2007Barker J.N.W.N. Palmer C.N.A. Zhao Y. Liao H. Hull P.R. Lee S.P. 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: 564-567Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar)163 early onset, persistent ADAD1.7 × 10−537.7 (5.3–10.9)42German4(Ruether et al., 2006Ruether A. Stoll M. Schwarz T. Schreiber S. Folster-Holst R. Filaggrin loss-of-function variant contributes to atopic dermatitis risk in the population of Northern Germany.BrJ Dermatol. 2006; 155: 1093-1094Crossref PubMed Scopus (83) Google Scholar)272 children with ADAD2.01 × 10−87.1 (3.41–14.78)35German5(R501X only typed)f(Ruether et al., 2006Ruether A. Stoll M. Schwarz T. Schreiber S. Folster-Holst R. Filaggrin loss-of-function variant contributes to atopic dermatitis risk in the population of Northern Germany.BrJ Dermatol. 2006; 155: 1093-1094Crossref PubMed Scopus (83) Google Scholar)338 triosAD0.00163.59 (1.75–6.58)14.2 (R501X only)Scottish(Dundee BREATHE)(Palmer et al., 2006Palmer C.N. Irvine A.D. Terron-Kwiatkowski A. Zhao Y. Liao H. Lee S.P. 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: 441-446Crossref PubMed Scopus (2088) Google Scholar)279 (children recruited through asthma clinics)AD + asthma4.8 × 10−113.3 (2.0–5.6)23German6(Weidinger et al., 2006Weidinger S. Illig T. Baurecht H. Irvine A.D. 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: 214-219Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar)476 trios (recruited though hospital-based dermatology clinics)AD5.1 × 10−8Not calculated22.75Allergic sensitization2.3 × 10−7Not calculatedTotal IgE9.8 × 10–8Not calculatedAsthma0.0003Not calculatedPalmar hyperlinearity5.9 × 10−6Not calculatedExtrinsic AD9.3 × 10−8Not calculatedGerman7(Stemmler et al., 2007Stemmler S. Parwez Q. Petrasch-Parwez E. Epplen J.T. Hoffjan S. Two common loss-of-function mutations within the filaggrin gene predispose for early onset of atopic dermatitis.J Invest Dermatol. 2007; 127: 722-724Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar)378 patients with AD (210 onset <2years)Onset <2yearsAll AD7.6 × 10−7Not calculated21.3German8(Weidinger et al., 2007Weidinger S. Rodrguez 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: 724-726Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar)274 adultsADIgEAsthmaRhinitisIntrinsic eczema4.9 × 10−50.0102.5 × 10−62.4 × 10−5No association3.53 (1.92–6.48)Not calculatedNot calculatedNot calculatedNo association21.1Early onset, 29.7German9(GENUFAD cohort)(Marenholz et al., 2006Marenholz 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: 866-871Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar)490 nuclear families903 cases with moderate to severe eczemaEczema1.9 × 10−9Not calculated18.6Eczema + asthma0.00042Not calculatedEczema + allergic rhinitis2.5 × 10−5Not calculatedEczema + increased IgE1.9 × 10−9Not calculatedGerman10(MAS cohort)(Marenholz et al., 2006Marenholz 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: 866-871Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar)871 children, population-based, longitudinal study up to 10years189 eczema118 asthmaEczema (n = 155)3.5 × 10−53.73 (1.98–7.02)16.7Nonatopic eczema(n = 63)0.000653.94 (1.7–8.9)Not recordedEczema + asthma(n = 40)5.4 × 10−86.21 (2.6–14.8)25Eczema + rhinitis(n = 44)1.5 × 10−54.75 (2.0–11.6)20Danish (COPSAC)11(Palmer et al., 2006Palmer C.N. Irvine A.D. Terron-Kwiatkowski A. Zhao Y. Liao H. Lee S.P. 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: 441-446Crossref PubMed Scopus (2088) Google Scholar)142 (children born to asthmatic mothers)AD<0.00012.8 (1.7–4.5)17.5Genetic analysis models: 1linkage analysis; 2case-control 2; 3case-control 2; 4case-control 2; 5case-control 2; 6transmission disequilibrium test; 7transmission disequilibrium test; 8case-control 2; 9case-control 2; 10family-based association; kcase-control 2; 11case-control 2. AD, atopic dermatitis; BREATHE; COPSAC, Copenhagen Prospective Study on Atopy in Children; GENUFAD, Genetic Studies in Nuclear Families with Atopic Dermatitis; MAS, Multicenter Allergy Study; NA, not applicable. Open table in a new tab Genetic analysis models: 1linkage analysis; 2case-control 2; 3case-control 2; 4case-control 2; 5case-control 2; 6transmission disequilibrium test; 7transmission disequilibrium test; 8case-control 2; 9case-control 2; 10family-based association; kcase-control 2; 11case-control 2. AD, atopic dermatitis; BREATHE; COPSAC, Copenhagen Prospective Study on Atopy in Children; GENUFAD, Genetic Studies in Nuclear Families with Atopic Dermatitis; MAS, Multicenter Allergy Study; NA, not applicable. Given such a strong gene effect, and given that these same alleles cause the distinct phenotype of ichthyosis vulgaris in a semidominant inheritance pattern (Smith et al., 2006Smith F.J. Irvine A.D. Terron-Kwiatkowski A. Sandilands A. Campbell L.E. Zhao Y. et al.Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.Nat Genet. 2006; 38: 337-342Crossref PubMed Scopus (755) Google Scholar), it is reasonable to ask whether the phenotypic characteristics of eczema related to FLG null alleles can in any way be dissected out from the broad and inclusive concept of eczema suggested by current guidelines. Subcategorization of eczema based on elevated circulating specific IgE levels (into atopic and nonatopic, or extrinsic and intrinsic forms) has been widely suggested, but it has failed to increase our predictive ability in terms of phenotype or course of disease (Flohr et al., 2004Flohr C. Johansson S.G. Wahlgren C.F. Williams H. How atopic is atopic dermatitis?.J Allergy Clin Immunol. 2004; 114: 150-158Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). In particular, elevated IgE levels are less relevant in community-based studies than in hospital-based studies (Flohr et al., 2004Flohr C. Johansson S.G. Wahlgren C.F. Williams H. How atopic is atopic dermatitis?.J Allergy Clin Immunol. 2004; 114: 150-158Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). Could the presence or absence of FLG null alleles help define sub-phenotypes and predict the course of eczema? Examination of the early data allows a degree of cautious interpretation as to the precise contribution of FLG null alleles to eczema phenotypes and to the consideration of possible genotype–phenotype correlates. Within cohorts that have been ascertained through attendance of people with eczema at dermatology clinics, some recurrent themes emerge. Two large series of adult patients with AD presenting to hospital clinics show a high frequency of FLG null carrier rates in adults who have persistent AD with onset within the first 2years (29.7% in a German cohort (Weidinger et al., 2007Weidinger S. Rodrguez 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: 724-726Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar), and 42% in an English cohort (Barker et al., 2007Barker J.N.W.N. Palmer C.N.A. Zhao Y. Liao H. Hull P.R. Lee S.P. 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: 564-567Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar)). These observations suggest that individuals with eczema who carry FLG null alleles could be more likely to have early onset and persistent disease, although controls with late-onset eczema and cohort studies are needed for further proof of such a notion. In well-characterized eczema cohorts from Munich, these alleles predispose to elevated IgE as a secondary trait (Weidinger et al., 2006Weidinger S. Illig T. Baurecht H. Irvine A.D. 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: 214-219Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar; Weidinger et al., 2007Weidinger S. Rodrguez 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: 724-726Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). This predisposition was also seen in the extended Genetic Studies in Nuclear Families with Atopic Dermatitis cohort (Marenholz et al., 2006Marenholz 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: 866-871Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar) and in relation to “extrinsic” AD (AD plus sensitization determined by positive skin-prick testing or specific IgE elevation) (Weidinger et al., 2007Weidinger S. Rodrguez 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: 724-726Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). These findings may reflect the more severe spectrum of disease seen in hospital studies, where elevated IgE is more commonly found (Flohr et al., 2004Flohr C. Johansson S.G. Wahlgren C.F. Williams H. How atopic is atopic dermatitis?.J Allergy Clin Immunol. 2004; 114: 150-158Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar), and it is interesting that in a birth-cohort study, FLG-null status was also strongly associated with nonatopic eczema (Marenholz et al., 2006Marenholz 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: 866-871Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar). Thus, elevated circulating IgE may be primarily an epiphenomenon that is a proxy for severity in eczema and is therefore more represented in hospital-ascertained series (Flohr et al., 2004Flohr C. Johansson S.G. Wahlgren C.F. Williams H. How atopic is atopic dermatitis?.J Allergy Clin Immunol. 2004; 114: 150-158Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). These early data hint at possible discriminating features of eczema associated with FLG null alleles. These early data hint at possible discriminating features of eczema associated with FLG null alleles. Although the relationship between FLG null alleles and asthma remains to be fully understood, in eczema cohorts where asthma status has been ascertained there is a consistent additional association with asthma as a secondary trait (Marenholz et al., 2006Marenholz 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: 866-871Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar; Weidinger et al., 2006Weidinger S. Illig T. Baurecht H. Irvine A.D. 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: 214-219Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar; Weidinger et al., 2007Weidinger S. Rodrguez 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: 724-726Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). The more informative cohorts in this regard are those ascertained through a diagnosis of asthma, and population-based cohorts. In the Dundee BREATHE cohort, the association of FLG with asthma was entirely limited to the subgroup with a coincident history of eczema, with no association between FLG alleles and asthma in the absence of eczema (Palmer et al., 2006Palmer C.N. Irvine A.D. Terron-Kwiatkowski A. Zhao Y. Liao H. Lee S.P. 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: 441-446Crossref PubMed Scopus (2088) Google Scholar). Similarly, in the German Multicenter Allergy Study cohort, FLG alleles had no association with asthma or allergic sensitization in the absence of prior eczema (Marenholz et al., 2006Marenholz 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: 866-871Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar). Importantly, this study also observed an additional risk of asthma in patients homozygous for FLG null alleles and calculated a striking population attributable risk factor of 20.6% for FLG null alleles for the phenotype eczema plus asthma (Marenholz et al., 2006Marenholz 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: 866-871Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar). These data suggest a sequence of phenotypic manifestations rather than individual susceptibilities to each of these manifestations of atopy and also allow speculation that early control of eczema may have an impact on future development of asthma, a concept that has already begun to be explored in studies such as the Early Treatment of the Atopic Child study (Warner, 2001Warner J.O. A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months’ treatment and 18 months’ posttreatment follow-up.J Allergy Clin Immunol. 2001; 108: 929-937Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). Taken together, these early data hint at possible discriminating features of eczema associated with FLG null alleles: that the eczema is more strongly associated with asthma, has associated hyperlinearity of the palms, and is more likely to be persistent into adulthood. An additional association with elevated IgE is also possible but not yet clear. This tentative analysis will doubtless be tempered as additional data become available, but it suggests a starting point to explore genotype–phenotype correlations. It should also be noted that although these carefully phenotyped cohorts where participants have been recruited through a diagnosis of eczema are very informative, they are unable to fully answer the question of what (if anything) is different about FLG-related eczema versus non-FLG-related eczema, nor can they determine the relative risk of FLG null alleles to asthma, atopy, and rhinitis (if any) per se. Large longitudinal or cross-sectional population-based cohorts that have been typed for all FLG variants will facilitate the dissection of these phenotypic characteristics and will enable researchers to compare and contrast FLG phenotypes versus others to test these speculations. Given the xerotic phenotype of ichthyosis vulgaris (Smith et al., 2006Smith F.J. Irvine A.D. Terron-Kwiatkowski A. Sandilands A. Campbell L.E. Zhao Y. et al.Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.Nat Genet. 2006; 38: 337-342Crossref PubMed Scopus (755) Google Scholar), which is seen in many eczema sufferers, future studies observing additional physical parameters of skin barrier function, such as the degree of skin hydration, the rate of transepidermal water loss, and susceptibility to skin irritation, may help to test the hypothesis of a “dry or defective barrier” type of FLG-related eczema. The pharmacogenetic significance of filaggrin status in predicting possible treatment responses to interventions such as emollients, soap substitution, water softening, or pharmacological intervention, and whether such interventions alter the disease trajectory, will also be worth examining. To date, filaggrin has not been shown to be a susceptibility factor for eczema in non-European populations. There are a few possible explanations for this, including the fact that the currently known recurrent mutations either are not present or are present at very low levels in many non-European populations (Palmer et al., 2006Palmer C.N. Irvine A.D. Terron-Kwiatkowski A. Zhao Y. Liao H. Lee S.P. 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: 441-446Crossref PubMed Scopus (2088) Google Scholar). Also, except in Japan, few research groups have established data sets of non-European eczema patients for genetic analysis. The technical difficulties of sequencing filaggrin may mean that it will take some time to determine the role of FLG mutations in populations outside of Europe. The incomplete penetrance of these alleles also merits further attention and is presumably explained by both genetic and environmental modifiers. Possible genetic modifiers of FLG null-allele penetrance include SPINK5 (Walley et al., 2001Walley A.J. Chavanas S. Moffatt M.F. Esnouf R.M. Ubhi B. Lawrence R. et al.Gene polymorphism in Netherton and common atopic disease.Nat Genet. 2001; 29: 175-178Crossref PubMed Scopus (337) Google Scholar) and SCCE (Vasilopoulos et al., 2004Vasilopoulos Y. Cork M.J. Murphy R. Williams H.C. Robinson D.A. Duff G.W. et al.Genetic association between an AACC insertion in the 3UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis.J Invest Dermatol. 2004; 123: 62-66Crossref PubMed Scopus (130) Google Scholar), both of which have been associated with eczema and both of which are plausibly involved in controlling filaggrin processing. Much has been learned in a short time about the role of FLG status in eczema. Much more needs to be understood about its function before this knowledge can be translated directly into patient benefit. The author states no conflict of interest. The author wishes to thank Hywel Williams for critical reading of the manuscript.
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