Deep palmar phenotyping in atopic eczema: patterns associated with <i>filaggrin</i> variants, disease severity and barrier function in a South Asian population

Thomas, Barry; Tan, X.L.; Duijvenboden, Stefan van; Hogan, Sarah; Hughes, Aaron; Tawfik, Soha S; Dhoat, Sasha; Atkar, Ravinder; Robinson, Elizabeth J; Rahman, Syedia R; Rahman, Samiha; Ahmed, Raju; Begum, Rumena; Khanam, Habiba; Bourne, Emma; Wozniak, Eva; Mein, Charles A.; Kelsell, David P.; O’Toole, Edel A.

doi:10.1093/bjd/ljad036

Cited by 4 publications

(1 citation statement)

References 31 publications

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“…Bangladeshi children and young adults age 0-30 with AE were recruited as part of a wider study at the Royal London Hospital and underwent clinical phenotyping and FLG genotyping as previously described (Thomas et al, 2023). This study was approved by the local ethics committee: Hampstead Regional Ethics Committee reference 18/LO/0018; Patients and/or parents gave written informed consent before participation in the study.…”

Section: Methodsmentioning

confidence: 99%

Reduced Filaggrin expression induces dysregulated intracellular signalling in atopic eczema

Hughes,

Coppock,

Tachie-Menson

et al. 2024

Preprint

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Atopic eczema (AE) is the most common inflammatory dermatosis, affecting up to 20% of children. Loss of function mutations in the Filaggrin (FLG) gene are the most strongly implicated genetic risk factor for AE, but little is known about the signalling pathways altered in response to loss of FLG. To explore the downstream effects of loss of FLG on the cellular environment, we combined RNAseq analysis of siRNA knockdown of normal human keratinocytes and analysis of tape strip (TS) samples from AE patients who were clinically phenotyped and genotyped for FLG mutation status. RNA-seq analysis revealed an increase in BMP signalling following FLG KD, which we validated in vivo using TS samples and biopsies. Recombinant BMP2 or BMP6 increased FLG and suprabasal keratin expression in vitro. Phosphoproteomic analysis identified 237 significantly differentially phosphorylated proteins following FLG KD. Kinase enrichment analysis identified downregulation of ERK1/2 and AKT1 signalling which was confirmed in AE biopsies. cFOS was downregulated following FLG KD and correlated with FLG expression in repository datasets. cFOS was downregulated following BMP6 treatment, implying that cFOS may be an important link between FLG and BMP signalling. Finally, proteomic analysis of TS samples identified altered desmosomal expression and phosphorylation following either loss of FLG or increased BMP signalling. Therefore, we have identified a SMAD1/Filaggrin/AKT axis as a potential therapeutic avenue in AE.

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Section: Methodsmentioning

confidence: 99%

Reduced Filaggrin expression induces dysregulated intracellular signalling in atopic eczema

Hughes,

Coppock,

Tachie-Menson

et al. 2024

Preprint

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Loss-of-function FLG mutations are associated with reduced history of acne vulgaris in a cohort of patients with atopic eczema of Bangladeshi ancestry in East London

Hughes,

Barbosa,

Cernova

et al. 2024

Clinical and Experimental Dermatology

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Acne vulgaris (AV) is the eighth most common non-fatal disease globally. Previous work identified an association between AV and increased Filaggrin (FLG) expression in the follicular epidermis, but further work did not find a clear link between loss of function (LoF) Filaggrin gene (FLG) mutations and protection from AV. In this work we aimed to explore any association between AV and FLG LoF mutations using a cohort of genotyped Bangladeshi patients with atopic eczema (AE) in East London. Retrospective notes review was performed on 245 patients who had been genotyped for FLG LoF mutations and undergone clinical assessment. The Chi squared or Fisher’s exact test was used to determine differences between groups. We found a significant reduction in history of AV in AE patients with FLG LoF mutations relative to AE patients without FLG mutations (p = 0.02). We showed a non-significant reduction in AV diagnosis in patients with impaired barrier function (measured by trans epidermal water loss) and palmar hyperlinearity. We found that patients with severe AE were less likely to have a history of AV only if they had an existing FLG LoF mutation (p = 0.02). In the context of AE, our work suggests that FLG LoF mutations protect patients from developing AV.

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Skin barrier dysfunction associates with type 2 inflammatory diseases: Evidence from a birth cohort

Abreu,

Mendes,

Silva

et al. 2024

Pediatric Allergy Immunology

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Deep palmar phenotyping in atopic eczema: patterns associated with filaggrin variants, disease severity and barrier function in a South Asian population

Cited by 4 publications

References 31 publications

Reduced Filaggrin expression induces dysregulated intracellular signalling in atopic eczema

Reduced Filaggrin expression induces dysregulated intracellular signalling in atopic eczema

Loss-of-function FLG mutations are associated with reduced history of acne vulgaris in a cohort of patients with atopic eczema of Bangladeshi ancestry in East London

Skin barrier dysfunction associates with type 2 inflammatory diseases: Evidence from a birth cohort

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