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Журнал "Здоров`я дитини" 1 (60) 2015

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Single-nucleotide polymorphism (rs11204981) in filaggrin gene (FLG) and its functional meaning for asthma among children with eczema

Автори: Pavlyk O., Iemets O., Stroy D., Volosovets O., Krivopustov S., Dosenko V. - O. Bogomolets National Medical University, Kiev, Ukraine

Рубрики: Педіатрія/Неонатологія

Розділи: Клінічні дослідження

Версія для друку


Filaggrin is a major structural protein in the stratum corneum involved in the terminal differentiation of the epidermis and formation of the skin barrier [7]. The FLG gene is located within the epidermal differentiation complex, a region on chromosome 1q21. Mutations in the filaggrin gene are the most significant known genetic factor for the development of atopic dermatitis [1]. Genetic variants (SNPs) in FLG also confer risk for the associated allergic diseases such as asthma [2,5,6,8,9]. Researches highlighted the importance of skin barrier function in the pathogenesis of atopic diseases and have motivated a surge in research characterizing the filaggrin-deficient skin barrier and its consequences. This reduction in barrier function may allow for the development of inflammation due to the increased penetration of allergen through the skin allowing IgE sensitization. Studies of functional significance of genetic variants in FLG showed that this gene is likely to contribute to mechanisms by which a quantitative reduction in intracellular filaggrin (mRNA expression) levels results in the paracellular barrier defects [3].

Materials and methods

All children had symptoms of asthma, eczema or symptoms of eczema in anamnesis, allergic rhinitis, or at least one positive skin prick test result to a panel of 15 aeroallergens. An SNP rs11204981 in FLG, which was located in promoter region, was selected for genotyping, as it hypothetically can affect expression of FLG mRNA and is reported to be common in European populations. 

 Genotyping for FLG (rs11204981) was performed in the following populations: patients with asthma, N = 100; ages 5-18 years (8 ± 2,1), and control group, N = 100; ages 5–18 years (12 ± 2,1) using Real-time PCR. Level of mRNA expression was estimated using reverse transcription following real-time PCR.


We found that SNP was in Hardy-Weinberg equilibrium. Our main results are as follows: 5% of patients and 2% of control group had minor allele (AA)  (p> 0,05 by χ2-test, OR – 2,28 (95%CI 0,42-12,2),  27% and 36% of patients and control group, respectively, had heterozygous allele (GA) (p> 0,05 by χ2-test , OR – 1,69 (95%CI 0,92-3,1)  and 67% and 61%  had major allele (GG) (p>0,05 by χ2-test). Variants with the AA genotype of the FLG rs11204981 were found to be 2,4 times more frequent among patients than in control group. 

We also found that the level of mRNA FLG expression in GG genotype is 22,8 ± 11,67 (p>0.05 compared to AA genotype), 92,95 ±  35,3 in  GA genotype (p<0.05 compared to GG genotype) and 21,8 ±  13,4 in AA genotype (p>0.05 compared to GA genotype). Thus, heterozygous variant has significantly higher expression of filaggrin in buccal epithelium.


Evidence from the literature has established that epidermal barrier function plays a critical role in eczema and possibly in the phenotype of eczema plus asthma. The combination of eczema plus asthma may represent a distinct endophenotype with unique pathogenic and prognostic implications. Identification of risk factors that may modify the risk of asthma among children with eczema is important. In addition, improved understanding of the relationship between eczema and asthma may provide mechanistic insights into the pathogenesis of asthma. We explored the relationship of childhood eczema plus asthma with epithelial protein encoded on 1q21 as well as with data from RNA expression studies and allele frequency differences in asthmatic populations. We demonstrated a possible connection between an SNP in FLG and eczema plus asthma among children. The AA genotype of the rs11204981 SNP conferred an approximately 2,4 times increased risk for eczema plus asthma phenotype. Findings for RNA filaggrin expression in buccal epithelium appear to be related to FLG polymorphism. Thus FLG polymorphism may affect filaggrin expression in the skin.

In this article, we determined the frequency of the rs11204981 SNP and showed that minor allele occurs 2,4 times more frequently among patients, although there was no statistical significance. Association of genotype with clinical parameters also was not established previously. Some researchers demonstrated assotiation of an increased risk of developing atopic dermatitis with other FLG polymorphisms, namely Weidinger S., Saffron A.G. (2013),  Lambert M.H. et al., (2010). In particular, positive associations of rs2184951 and rs12730241 [6] with asthma and allergic diseases were determined. Polymorphism rs11204981 has been widely studied in the European population and therefore was chosen by us for this research.

However, in the study of the expression level of the filaggrin mRNA we were able to show that this polymorphism is functional and affects the expression of filaggrin. mRNA FLG expression in heterozygote is 4 times higher than common homozygous genotype (p<0.05) and 4,3 times higher than homozygous risk genotype (p>0.05).


Our research has demonstrated functional significance of GA genotype of FLG polymorphism, thus suggesting that this polymorphism may have a predictive value in the development of asthma and eczema affecting the expression of that gene.

Thereby, polymorphisms in FLG may independently serve as useful markers to predict the development of asthma among children with eczema.

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