Dataset Information

Correlation of age-of-onset of Atopic Dermatitis with Filaggrin loss-of-function variant status.

ABSTRACT: The genetic background of Atopic Dermatitis (AD) with chronic pruritus is complex. Filaggrin (FLG) is an essential gene in the epidermal barrier formation s. Loss-of-function (LOF) variants in FLG associated with skin barrier dysfunction constitute the most well-known genetic risk factor for AD. In this study, we focused on the frequency and effect of FLG loss-of-function variants in association with self-reported age-of-onset of AD. The dataset consisted of 386 whole-genome sequencing (WGS) samples. We observe a significant association between FLG LOF status and age-of-onset, with earlier age of onset of AD observed in the FLG LOF carrier group (p-value 0.0003, Wilcoxon two-sample test). We first tested this on the two most prevalent FLG variants. Interestingly, the effect is even stronger when considering all detected FLG LOF variants. Having two or more FLG LOF variants associates with the onset of AD at 2 years of age. In this study, we have shown enrichment of rare variants in the EDC region in cases compared with controls. Age-of-onset analysis shows not only the effect of the FLG and likely EDC variants in terms of the heightened risk of AD, but foremost enables to predict early-onset, lending further credence to the penetrance and causative effect of the identified variants. Understanding the genetic background and risk of early-onset is suggestive of skin barrier dysfunction etiology of AD with chronic pruritus.

SUBMITTER: Smieszek SP

PROVIDER: S-EPMC7026049 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Correlation of age-of-onset of Atopic Dermatitis with Filaggrin loss-of-function variant status.

Smieszek S P SP Welsh S S Xiao C C Wang J J Polymeropoulos C C Birznieks G G Polymeropoulos M H MH

Scientific reports 20200217 1

The genetic background of Atopic Dermatitis (AD) with chronic pruritus is complex. Filaggrin (FLG) is an essential gene in the epidermal barrier formation s. Loss-of-function (LOF) variants in FLG associated with skin barrier dysfunction constitute the most well-known genetic risk factor for AD. In this study, we focused on the frequency and effect of FLG loss-of-function variants in association with self-reported age-of-onset of AD. The dataset consisted of 386 whole-genome sequencing (WGS) sam ...[more]

PMID: 32066784

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Project description:Importance:Atopic dermatitis (AD) is a common chronic illness that has been associated with variation in the filaggrin gene (FLG). Four variants are most often evaluated. Objectives:To comprehensively describe and compare results from targeted sequencing of FLG loss-of-function (LoF) variants in children of African and European ancestry and the association of these variants with onset and persistence of AD. Design, Setting, and Participants:This prospective US cohort study assessed the genetic subcohort of the Pediatric Eczema Elective Registry (PEER). Children with mild to moderate AD were included in the analysis. Massively parallel sequencing (MPS) was used to focus on FLG LoF variation in white and African American children. Patients were enrolled from June 2005 through July 2017. Data were analyzed from January 25 through May 10, 2019. Main Outcomes and Measures:Associations of FLG LoF variation with white and African American ancestry and with the risk and persistence of AD. Results:A total of 741 children were included in the analysis (394 [53.2%] female and 347 [46.8%] male; mean [SD] age at onset, 1.97 [2.72] years); of these, 394 (53.2%) were white, 326 (44.0%) were African American, and 21 (2.8%) were of other ancestries. Using MPS technology, 23 FLG LoF variants were found in children with AD. The prevalence of FLG LoF variants was 177 participants (23.9%) in the full cohort, 124 white participants (31.5%), and 50 African American participants (15.3%). The odds ratio for carrying any FLG LoF variant in a white child compared with an African American child with AD was 2.44 (95% CI, 1.76-3.39). Some FLG LoF variants are only found in children of a specific ancestry (eg, p.S3316* and p.R826* were not seen in white patients). Children with an FLG LoF were more likely to have persistent AD (odds ratio, 0.67; 95% CI, 0.56-0.80). Conclusions and Relevance:The FLG LoF variants in a US cohort of children with mild to moderate AD differ significantly by race and their association with the persistence of AD. Conventional testing of the 4 frequently evaluated variants is inadequate. Any planned genetic diagnostic test for AD based on FLG LoF variants must be inclusive and not rely on the most frequently studied variants.

Dataset Information

Correlation of age-of-onset of Atopic Dermatitis with Filaggrin loss-of-function variant status.

Publications

Correlation of age-of-onset of Atopic Dermatitis with Filaggrin loss-of-function variant status.

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