Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa. Electronic address: .
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 10/2013; 133(3). DOI: 10.1016/j.jaci.2013.09.015
Source: PubMed


Atopic dermatitis (AD) is a common skin disease characterized by recurrent episodes of itching. Genetic variation associated with the persistence of AD has not been described for African American subjects.
We sought to evaluate genetic variation of filaggrin-2 (FLG2) in African American subjects with AD.
We evaluated a multiyear prospective cohort study of African American children with AD with respect to FLG2 variation based on whole-exome sequencing, followed by a targeted analysis. We ultimately evaluated the association of rs12568784 and rs16833974 with respect to the persistence of AD symptoms over time.
Whole-exome analysis was conducted on 60 subjects, revealing a premature stop codon in exon 3 at S2377X (rs12568784) and X2392S (rs150529054) and a large exon 3 deletion mutation, Q2053del224. On the basis of a priori criteria, we then studied rs12568784, rs16833974 (H1249R), and Q2053del224. We noted that patients with S2377X (odds ratio [OR], 0.44; 95% CI, 0.25-0.46) and H1249R (OR, 0.23; 05% CI, 0.12-0.46) were significantly less likely to be free of symptoms of AD, and Q2053del224 (OR, 0.54; 95% CI, 0.16-1.80) trended toward this outcome. S2377X and H1249R were in high linkage disequilibrium (D' = 0.95).
In an African American cohort with AD, FLG2 mutations were associated with more persistent AD. This is the first finding of genetic variation of a skin barrier protein in subjects of African ancestry with AD.

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    • "These genes are very similar to one another with respect to structure and function, and lie in close proximity to each other in the EDC (Marenholz et al., 2011;Henry et al., 2012;Pellerin et al., 2013). Based on prior experience with FLG, it has been hypothesized that a stop-gain (null) mutation in exon 3 of any of the SFTP genes will result in decreased or absent protein production (Henry et al., 2012;Marenholz et al., 2011;Margolis et al., 2014). "
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    ABSTRACT: Abbreviations: AD, atopic dermatitis; FLG, Filaggrin; MAF, minor allelic frequency; SFTP, S100-fused-like protein
    Journal of Investigative Dermatology 03/2014; 134(8). DOI:10.1038/jid.2014.126 · 7.22 Impact Factor
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    ABSTRACT: Atopic dermatitis (AD) is a chronic inflammatory skin condition with complex etiology that is dependent upon interactions between the host and the environment. Acute skin lesions exhibit the features of a Th2-driven inflammatory disorder, and many patients are highly atopic. The skin barrier plays key roles in immune surveillance and homeostasis, and in preventing penetration of microbial products and allergens. Defects that compromise the structural integrity or else the immune function of the skin barrier play a pivotal role in the pathogenesis of AD. This article provides an overview of the array of molecular building blocks that are essential to maintaining healthy skin. The basis for structural defects in the skin is discussed in relation to AD, with an emphasis on filaggrin and its genetic underpinnings. Aspects of innate immunity, including the role of antimicrobial peptides and proteases, are also discussed.
    Current Allergy and Asthma Reports 05/2014; 14(5):433. DOI:10.1007/s11882-014-0433-9 · 2.77 Impact Factor
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    ABSTRACT: Filaggrin-2 is a member of the S100 fused-type protein family, and the structural features and expression of filaggrin-2 are similar to those of profilaggrin, a protein essential for keratinization. In the present study, we investigated the expression profile of filaggrin-2 in patients with skin diseases using antibodies against the repetitive region of filaggrin-2. In tissue samples from patients with skin diseases which are associated with a decrease in filaggrin, including ichthyosis vulgaris, atopic dermatitis and psoriasis vulgaris, the expression level of filaggrin-2 was markedly decreased compared to that in normal skin samples. In contrast, the expression of filaggrin-2 increased in parallel with that of filaggrin in samples of tissue from patients with skin diseases associated with hyperkeratosis, such as lichen planus and epidermolytic ichthyosis. Interestingly, filaggrin-2 signals were observed in slightly higher layers of the epidermis in comparison to those of filaggrin. Similarly, the expression of filaggrin-2 proteins was induced slightly later than filaggrin in the cultured keratinocytes. These findings suggest that filaggrin-2 may play an overlapping role with filaggrin in epithelial cornification; however, it may also have a partially distinct role in the molecular processes of cornification.
    Biochemical and Biophysical Research Communications 05/2014; 449(1). DOI:10.1016/j.bbrc.2014.04.165 · 2.30 Impact Factor
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