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Loss-of-function variants within the filaggrin gene (FLG) increase the risk of atopic dermatitis. FLG also demonstrates intragenic copy number variation (CNV), with alleles encoding 10, 11, or 12 filaggrin monomers; hence, CNV may affect the amount of filaggrin expressed in the epidermis. A total of 876 Irish pediatric atopic dermatitis cases were compared with 928 population controls to test the hypothesis that CNV within FLG affects the risk of atopic dermatitis independently of FLG-null mutations. Cases and controls were screened for CNV and common FLG-null mutations. In this population the 11-repeat allele was most prevalent (allele frequency 51.5%); the 10-repeat allele frequency was 33.9% and the 12-repeat allele frequency was 14.6%. Having excluded FLG mutation carriers, the control group had a significantly higher number of repeats than cases (χ(2) P=0.043), and the odds ratio of disease was reduced by a factor of 0.88 (95% confidence interval 0.78-0.98, P=0.025) for each additional unit of copy number. Breakdown products of filaggrin were quantified in tape-stripped stratum corneum from 31 atopic dermatitis patients and urocanic acid showed a positive correlation with total copy number. CNV within FLG makes a significant, dose-dependent contribution to atopic dermatitis risk, and therefore treatments to increase filaggrin expression may have therapeutic utility.

Background: IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy., Objective: To investigate the association between filaggrin loss-of-function mutations and peanut allergy., Methods: Case-control study of 71 English, Dutch, and Irish oral food challenge-positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥ 8 mm and/or peanut-specific IgE ≥ 15 kUL(-1)) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis., Results: Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge-positive patients (P = 3.0 × 10(-6); odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study (P = 5.4 × 10(-5); odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant (P = .0008) after controlling for coexistent atopic dermatitis., Conclusion: Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Filaggrin (FLG) has a central role in the pathogenesis of atopic dermatitis (AD). FLG is a complex repetitive gene; highly population-specific mutations and multiple rare mutations make routine genotyping complex. Furthermore, the mechanistic pathways through which mutations in FLG predispose to AD are unclear., Objectives: We sought to determine whether specific Raman microspectroscopic natural moisturizing factor (NMF) signatures of the stratum corneum could be used as markers of FLG genotype in patients with moderate-to-severe AD., Methods: The composition and function of the stratum corneum in 132 well-characterized patients with moderate-to-severe AD were assessed by means of confocal Raman microspectroscopy and measurement of transepidermal water loss (TEWL). These parameters were compared with FLG genotype and clinical assessment., Results: Three subpopulations closely corresponding with FLG genotype were identified by using Raman spectroscopy. The Raman signature of NMF discriminated between FLG-associated AD and non-FLG-associated AD (area under the curve, 0.94; 95% CI, 0.91-0.99). In addition, within the subset of FLG-associated AD, NMF distinguished between patients with 1 versus 2 mutations. Five novel FLG mutations were found on rescreening outlying patients with Raman signatures suggestive of undetected mutations (R3418X, G1138X, S1040X, 10085delC, and L2933X). TEWL did not associate with FLG genotype subgroups., Conclusions: Raman spectroscopy permits rapid and highly accurate stratification of FLG-associated AD. FLG mutations do not influence TEWL within established moderate-to-severe AD., (Copyright (c) 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Atopic eczema is a common inflammatory skin disease with multifactorial etiology. The genetic basis is incompletely understood; however, loss of function mutations in the filaggrin gene (FLG) are the most significant and widely replicated genetic risk factor reported to date. The first genome-wide association study in atopic eczema recently identified 2 novel genetic variants in association with eczema susceptibility: a single nucleotide polymorphism on chromosome 11q13.5 (rs7927894) and a single nucleotide polymorphism (rs877776) within the gene encoding hornerin on chromosome 1q21., Objective: To test the association of these 2 novel variants with pediatric eczema and to investigate their interaction with FLG null mutations., Methods: Case-control study to investigate the association of rs7927894, rs877776 and the 4 most prevalent FLG null mutations with moderate-severe eczema in 511 Irish pediatric cases and 1000 Irish controls. Comprehensive testing for interaction between each of the loci was also performed., Results: The association between rs7927894 and atopic eczema was replicated in this population (P = .0025, chi(2) test; odds ratio, 1.27; 95% CI, 1.09-1.49). The 4 most common FLG null variants were strongly associated with atopic eczema (P = 1.26 x 10(-50); combined odds ratio, 5.81; 95% CI, 4.51-7.49). Interestingly, the rs7927894 association was independent of the well-established FLG risk alleles and may be multiplicative in its effect. There was no significant association between rs877776 and pediatric eczema in this study., Conclusion: Single nucleotide polymorphism rs7927894 appears to mark a genuine eczema susceptibility locus that will require further elucidation through fine mapping and functional analysis., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: With an impressive series of replication studies, filaggrin (FLG) has become the gene with the most widely replicated association to atopic eczema (AE). However, studies published to date demonstrate differences concerning study design and strength of associations., Objectives: We sought to provide a general and overall estimate of FLG effect sizes and to estimate allele and carrier frequencies., Methods: We searched Medline and Institute for Scientific Information Web of Knowledge databases for relevant studies and abstracts from professional societies that were published through June 30, 2007. Initially, we accounted for different study types and evaluated an overall estimate for case-control and family studies. In a second step, we combined those 2 study types and used a random-effects analysis approach to calculate overall odds ratios (ORs). Tests of asymmetry were applied to detect potential publication bias., Results: Nine studies that met the inclusion criteria were included in the meta-analysis. For the combined genotype (R501X or 2282del4), we found an overall OR of 4.09 (95% CI, 2.64-6.33) from the case-control studies and a summary OR of 2.06 (95% CI, 1.76-2.42) from the family studies., Conclusion: The powerful effect of FLG variation on AE risk exceeds that of any other investigated candidate gene for AE thus far and makes FLG one of the strongest genes known to date for complex diseases., Clinical Implications: These results underline the importance of a genetically determined epidermal barrier disruption in AE.

We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi2 test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.

Mutations in the filament aggregating protein (filaggrin) gene have recently been identified as the cause of the common genetic skin disorder ichthyosis vulgaris (IV), the most prevalent inherited disorder of keratinization. The main characteristics of IV are fine-scale on the arms and legs, palmar hyperlinearity, and keratosis pilaris. Here, we have studied six Irish families with IV for mutations in filaggrin. We have identified a new mutation, 3702delG, in addition to further instances of the reported mutations R501X and 2282del4, which are common in people of European origin. A case of a 2282del4 homozygote was also identified. Mutation 3702delG terminates protein translation in filaggrin repeat domain 3, whereas both recurrent mutations occur in repeat 1. These mutations are semidominant: heterozygotes have an intermediate phenotype most readily identified by palmar hyperlinearity and in some cases fine-scale and/or keratosis pilaris, whereas homozygotes or compound heterozygotes generally have more marked ichthyosis. Interestingly, the phenotypes of individuals homozygous for R501X, 2282del4, or compound heterozygous for R501X and 3702delG, were comparable, suggesting that mutations located centrally in the filaggrin repeats are also pathogenic.