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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    • "There are many reasons to account for the difficulties in assessing pigmented patients with AD. Phenotypic variations secondary to genetic differences is one reason; for example, filaggrin-2 mutation variations in AD have been found in African-American patients, and have been associated with a more persistent disease course (Margolis et al., 2014; Torrelo, 2014). Another example is that pigmented skin has been shown to be less likely to develop erythema when exposed to irritants (Berardesca and Maibach, 2003). "
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    ABSTRACT: Background: Outcome measures for atopic dermatitis (AD) patients with pigmented skin have neither been developed nor validated. Objective: To compare the reliability and validity of four common AD outcome measures in patients with various levels of skin darkness. Method: The inter- and intra-rater reliability and construct validity of the EASI (Eczema Area and Severity Index), objective-SCORing Atopic Dermatitis (oSCORAD), Three Items Severity index (TIS) and Six Areas, Six Sites Atopic Dermatitis (SASSAD) were evaluated in 18 patients of various levels of skin darkness, using their full body photographs, by five trained clinicians. Results: The inter-rater reliability intraclass coefficient (ICCs) and 95% confidence intervals were poor for highly pigmented patients: EASI -054(-200 to .657), oSCORAD -089(-206 to .598), TIS -21(-24 to .147), SASSAD -071(-200 to .631); fair for mildly pigmented patients: EASI .464(140-839), oSCORAD .588(265-89), TIS.524(200-865), SASSAD .41(045-775); and fair to good for non-pigmented patients: EASI .64(330-908), oSCORAD .586(263-889), TIS .403(09-809), SASSAD .667(358-916). Erythema likely contributed to the inter-rater variability. Construct validity had significant correlations across all measures in non-pigmented patients, but no correlations in highly pigmented patients. Conclusion: AD outcome measures have poor reliability and validity in highly pigmented patients, with variations in erythema perception being a contributor.
    Full-text · Article · Aug 2015
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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
    Preview · Article · Mar 2014 · Journal of Investigative Dermatology
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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.
    No preview · Article · May 2014 · Current Allergy and Asthma Reports
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