Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum

Abstract

Background Loss-of-function null mutations R501X and 2282del4 in the skin barrier gene, filaggrin (FLG), represent the most replicated genetic risk factors for atopic dermatitis (AD). Associations have not been reported in African ancestry populations. Eczema herpeticum (ADEH) is a rare but serious complication of AD resulting from disseminated cutaneous HSV infections. Objective We aimed to determine whether FLG polymorphisms contribute to ADEH susceptibility. Methods Two common loss-of-function mutations plus nine FLG single nucleotide polymorphisms (SNPs) were genotyped in 278 European American AD patients, of whom 112 had ADEH, and 157non-atopic controls. Replication was performed on 339 African Americans. Results Significant associations were observed for both the R501X and 2282del4 mutations and AD among European Americans (P=1.46×10−5,3.87×10−5, respectively), but the frequency of the R501X mutation was three times higher (25.% vs 9%) for ADEH compared to AD without EH (odds ratio [OR]=3.4 (1.7–6.8), P=0.0002). Associations with ADEH were stronger with the combined null mutations (OR=10.1 (4.7–22.1), P=1.99×10−11). Associations with the R501X mutation were replicated in the African American population; the null mutation was absent among healthy African Americans, but present among AD (3.2%, P=0.035) and common among ADEH (9.4%; P=0.0049) patients. However, the 2282del4 mutation was absent among African American ADEH patients and rare (<1%) among healthy individuals. Conclusion The R501X mutation in the gene encoding filaggrin, one of the strongest genetic predictors of AD, confers an even greater risk for ADEH in both European and African ancestry populations, suggesting a role for defective skin barrier in this devastating condition. Clinical Implications The Filaggrin (FLG) R501X Mutation, a major risk factor for atopic dermatitis, confers a greater risk of the severe, HSV-associated complication, eczema herpeticum in diverse ethnic groups. Capsule Summary Mutations in the skin barrier function protein, filaggrin, are strong predictors of atopic dermatitis. This report demonstrates an even greater association between one of these mutations (R501X) and eczema herpeticum in ethnically diverse American populations.

Atopic Dermatitis

“…It is up to now unclear, whether viral warts or mollusca contagiosa are likewise more prevalent in AD. However, large studies have shown that it will be possible to identify patients at risk to develop eczema herpeticum on the basis of clinical, immunological and genetic informations 60,61 .…”

127 Proteomic analysis of filaggrin deficiency identifies molecular signatures characteristic of atopic eczema

“…49,50 Patients with AE have an increased susceptibility to both disseminated viral (eczema herpeticum) and bacterial skin infections, 51 and the risk of both is increased in FLG-deficient subjects. 52 Consistent with this, stress responses, namely type 1 interferonmediated anti-pathogenic deference, are overrepresented in the transcriptome of FLG-null and haplosufficient patients with AE, 12 and furthermore, type 1 interferon expression is increased in patients with eczema herpeticum. 53 Type 1 interferons are secreted after viral 54 or bacterial 55 infection and mediate both immunomodulatory responses and local cell-cycle regulation in part through activation of eIF2, 56 mTOR, and downstream p70-S6K/eIF4 signaling.…”

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“…They can be simultaneously triggered causing immune response. [32,33] The relationship between filaggrin and TH2 inflammation are shown in Figure 2. The homozygous FLG mutant carriers without filaggrin expression have severe and persistent allergic early-onset AD.…”