Abstract
Background FLG null variants of which 2282del4 and R501X are the most frequent in Caucasians are established risk factors for atopic dermatitis (AD) with an effect probably mediated through impairment of epidermal barrier. Among subjects with AD FLG defects are also consistently associated with asthma and allergic rhinitis (AR) but it is less clear to what extent these associations are also present independently from skin disease. The aim of the present study was to evaluate the role of 2282del4 and R501X in predisposing to these allergic phenotypes in a Polish population.Methodology2282del4 and R501X were typed among 3,802 participants of the Epidemiology of Allergic Diseases in Poland (ECAP) survey, a cross-sectional population-based study using ECRHS II and ISAAC questionnaires, and ambulatory examination.Principal FindingsThe FLG null variants were associated with AD (OR = 2.01, CI: 1.20–3.36, P = 0.007), allergic rhinitis (in particular persistent form, OR = 1.69, CI:1.12–2.54, P = 0.011), and asthma (in particular atopic asthma, OR = 2.22, CI:1.24–3.96, P = 0.006). Association with atopic asthma (but not persistent allergic rhinitis) was also present in the absence of AD, (OR = 2.02, CI: 1.07–3.81, P = 0.027) as well as in the absence of AD and history of broadly defined inflammatory skin disease (OR = 2.30, CI: 1.07–4.93, P = 0.03). Association to atopic asthma would have not been found if diagnosis was made by questionnaire only (OR = 1.15, CI: 0.58–2.32, P = 0.8). We did not observe an association between FLG variants and allergic sensitizations (P = 0.8) or total IgE. (P = 0.6).Conclusions/SignificanceIn a Polish population FLG 2282del4 and R501X carriage increases risk for development of AD and atopic asthma (also in the absence of AD or history thereof). This suggests that interventions aimed at restoring epidermal barrier may have a general role in asthma prophylaxis/treatment.
Highlights
Filaggrin gene (FLG) is strongly expressed in the granular cells of the epidermis leading to production of a large precursor protein profilaggrin
The FLG R501X variant is rare in a Polish population While analyzing the 3802 subjects from Epidemiology of Allergic Diseases in Poland (ECAP) cohort we identified 3629 wild type, 140 heterozygous and three homozygous 2282del4 genotypes as well as 30 heterozygous R501X genotypes
In order to verify relatively low frequency of R501X vs. 2282del4 variant in a Polish population we tested 510 samples randomly selected from an anonymous bank containing DNA isolated for the purpose of paternity tests [16]
Summary
Filaggrin gene (FLG) is strongly expressed in the granular cells of the epidermis leading to production of a large precursor protein profilaggrin. The N-terminal domain of profilaggrin is likely to have an additional function as it localizes to the nucleus All these processes are critical for creation of epidermal barrier with appropriate mechanical and biochemical properties [1]. In Caucasians two such variants are common: 2282del and R501X with originally reported carrier rates in general population of ,2 and 6%, respectively [2]. Both variants result in a complete loss of processed filaggrin due to premature termination codons within the first FLG repeat. FLG null variants of which 2282del and R501X are the most frequent in Caucasians are established risk factors for atopic dermatitis (AD) with an effect probably mediated through impairment of epidermal barrier. The aim of the present study was to evaluate the role of 2282del and R501X in predisposing to these allergic phenotypes in a Polish population
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