Atopic dermatitis and skin disease
Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum

https://doi.org/10.1016/j.jaci.2009.07.034Get rights and content

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. Atopic dermatitis eczema herpeticum (ADEH) is a rare but serious complication of AD resulting from disseminated cutaneous herpes simplex virus infections.

Objective

We aimed to determine whether FLG polymorphisms contribute to ADEH susceptibility.

Methods

Two common loss-of-function mutations plus 9 FLG single nucleotide polymorphisms were genotyped in 278 European American patients with AD, of whom 112 had ADEH, and 157 nonatopic controls. Replication was performed on 339 African American subjects.

Results

Significant associations were observed for both the R501X and 2282del4 mutations and AD among European American subjects (P = 1.46 × 10−5, 3.87 × 10−5, respectively), but the frequency of the R501X mutation was 3 times higher (25% vs 9%) for ADEH than for AD without eczema herpeticum (EH) (odds ratio [OR], 3.4; 1.7-6.8; P = .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 American subjects, but present among patients with AD (3.2%; P = .035) and common among patients with ADEH (9.4%; P = .0049). However, the 2282del4 mutation was absent among African American patients with ADEH 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.

Section snippets

Study participants and phenotypes

DNA was isolated from 278 unrelated European American patients with AD (112 with ADEH) and 157 healthy controls participating in the ADVN. The same set of markers was genotyped on 187 African American patients with AD (32 with ADEH) and 152 healthy controls. Baseline characteristics are presented in Table I.

Atopic dermatitis was diagnosed by using the US consensus conference criteria.17 Patients with ADEH were defined as patients with AD with at least 1 eczema herpeticum (EH) episode documented

Results

We compared the distribution of observed P values to the expected distribution under the null hypothesis of no genetic association, and concordant with findings reported in other European American populations,20 significant associations were observed for both the R501X and 2282del4 mutations and AD, with allele frequencies of the R501X allele among all patients with AD at 7.8% compared with1.3% among the healthy participants (odds ratio [OR], 7.1; 2.5-20.1; P = 1.46 × 10−5; Table II) and

Discussion

This study of FLG polymorphisms in 2 independent and ethnically diverse populations of patients with AD stratified by the serious complication, ADEH, demonstrated that the functional R501X mutation confers an added risk of ADEH, with an estimated effect size of nearly 13 among European American patients (P = 7.25 × 10−9), and this association was further replicated among African American patients (P = .0049). Furthermore, we observed a significant association between the 2282del4 mutation and

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Supported in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, and the Department of Health and Human Services under contract numbers HHSN266200400029C and HHSN266200400033C. K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program.

Disclosure of potential conflict of interest: M. Boguniewicz has consulted for Graceway and Unilever and has received research support from Novartis. L. C. Schneider has received research support from Novartis and the National Institutes of Health/National Institute of Allergy and Infectious Diseases. L. A. Beck owns stock in Wyeth, has received research support from the National Institutes of Health/National Institute of Allergy and Infectious Diseases and Centocor, and has provided legal consultation or expert witness testimony for GlycoMimetics, Anacor, and Magen. The rest of the authors have declared that they have no conflict of interest.

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