THE ROLE OF GENETIC POLYMORPHISM OF THE FILAGGRIN PROTEIN WITH ATOPIC MARCH PROGRESSION IN CHILDREN

The aim of the study. To determine the role of genetic polymorphism in the filaggrin gene R501XAA and 2282de4AA at atopic march progression in children. Materials and methods. 111 children aged 3 to 12 years with atopic dermatitis were selected and examined. As a result of genetic testing, it was found that 51 children with atopic dermatitis had polymorphism in the filaggrin gene. These patients were included in the main group. Another 60 children without polymorphism were in the control group. The filaggrin gene polymorphism was determined by THEORY AND PRACTICE OF SCIENCE: KEY ASPECTS 188 examining the buccal epithelium by Dellaporta method. Sensitization to allergens was established on the basis of the specific IgE level. The impact of the disease on the quality of life of children was performed using the CDLQI questionnaire (Children's Dermatology Life Quality Index). Results. In the course of molecular genetics research, R501X mutation was detected in 40 ((78.4 ± 5.76)%) children, 2282del4 polymorphism – in 4 ((7.8 ± 3.76)%) patients, and their combined variant R501X + 2282del4 – in 7 (13%), (7 ± 4.81)% patients. When determining the effect of filaggrin polymorphism on the clinical course of atopic dermatitis, the presence of the associative relationship was established with the following indicators: the early onset of the disease – χ = 33.2, mostly severe course – χ = 16.2, severe skin dryness – χ = 22.6, predominant sensitization to fungi – χ = 10.6 and house dust mites – χ = 12.2, violation of the skin microbiome – χ = 7.8. Conclusions. Early manifestation of atopic dermatitis in children is associated with the filaggrin protein gene polymorphism ((82.4 ± 5.33)%), which determines the risk of progression of the atopic march and the development of bronchial asthma in (38.0 ± 6.8)% of children.

Introduction. The prevalence of allergic diseases is steadily increasing around the world, and there is a tendency to increasing complexity and severity of allergic processes in childhood.
Recently, significant progress has been made in understanding the pathophysiology of allergy, through the use of molecular diagnostics, immunophenotyping, tissue engineering and the study of epidermal nanostructures.
These studies have shown that the basis of allergic processes is complex heterogeneous pathophysiological mechanisms, covering various phenotypes and endotypes of pathology, which determine the development and subsequent prognosis of the disease.
A special place in the structure of allergic diseases is occupied by atopic dermatitis (AD), which is one of the most common inflammatory skin diseases and occurs in children with a frequency of 15-20%. Beginning often at an early age, the disease has not only pronounced clinical manifestations, but also significantly affects the quality of life of the child.
Although the etiopathogenetic mechanisms that characterize the development of allergic pathology have been studied in great detail, the importance of nonimmune mechanisms in AM pathophysiology and development remains unclear.

SCIENTIFIC COLLECTION «INTERCONF» | № 58 189
Currently, the role of genetically determined disorders, which create an immunopathophysiological platform for the realization of atopy, hypersensitivity to allergens and non-specific stimuli, hyperproduction of inflammatory mediators in allergic conditions has been proved [1]. However, these pathogenetic aspects are not enough to fully explain the features of inflammatory processes in the skin that occur during AD and the atopic march (AM) progression. Probably, the disturbances at the molecular level underlie the inability of the epidermis to provide a barrier function and prevent transcutaneous penetration of allergens, which ultimately creates the conditions for the formation of chronic inflammation in the skin and bronchi.
Today the data on the participation of 26 genes in the development of atopic inflammation have been released. The most of them relate to a certain allergic condition [2]. According to GWAS guidelines (genome-wide association studies), genes associated with allergic diseases are divided into two groups: skin barrier genes and immune response genes. In some patients with allergic pathology, both directions intersect, so initiating a chain of inflammation that will be responsible for the development of certain clinical nosoforms -AD, bronchial asthma (BA), allergic rhinitis (AR)or their combination [3][4][5].
In the group of skin barrier genes, a special place is occupied by the filaggrin protein (filament aggregating protein -FLG), which is responsible for the regulation of epidermal homeostasis [6]. Precisely because of the filaggrin protein, the proteinlipid structure of the stratum corneum is formed, the differentiation of keratinocytes takes place, creating a barrier that prevents moisture loss and penetration of allergens and microorganisms [7]. FLG is a product of proteolytically altered prophylagrin, a precursor that contains 324 multiple filaggrin units and is found in keratohyalin granules. It is proved that the intermediate filament-associated protein combines keratin fibers in the epidermis. Under conditions of the allergic process, keratinocytes of the broken barrier secrete immune adjuvants that activate the maturation of Langerhans cells or dendritic cells, as well as affect their ability to direct the polarization of naive Th-lymphocytes and, accordingly, affect the Thresponse nature. The key structural proteins of the upper layer of the epidermis involved in keratinization are encoded on chromosome 1q21, the gene encoding filaggrin is found in this locus [8,9]. So, polymorphism in FLG gene is the most important genetic factor in AD development, and probably atopic march in general [10] due to the proved role of mutations in FLG gene at the level of 1q21, which causes violation of the filaggrin synthesis, inducing the development of not only AD but also BA [1,11]. The search for the role of the filaggrin protein defects in the development of BA in children is under way [8].
Currently, the active study of FLG gene polymorphism is under way and more than 40 mutations specific to different populations and races have been described today [12,13]. The most common mutations were in the third exon -2282del4 and R501X. In European regions, the most common variants are: R501X, 2282del4, S3247X, 3702delG, R2447X, and in Asian countries -3321delA (East Asia), and Q2417X (Taiwan and China). Interestingly, in Russia the polymorphism R501X, 2282del4, S3247X, R2447X occurs in patients with AD with different frequency, but the carriers of the mutation 3702delG are not detected at all [14,15]. These data clearly demonstrate the difference in FLG population genetics between Europe and Asia [16].
By prevalence, mutations in FLG gene on chromosome 1q21 occur in 50-60% of Europeans suffering from AD. At the same time, according to national studies, mutations in R501X and 2282del4 in FLG gene are observed in only 20.6% of patients with AD, which obviously does not reflect the real situation, but indicates insufficient involvement of molecular genetic analysis in AD diagnosis [17].
The question of the role of FLG polymorphism variants in the development of the atopic march remains open. According to existing data, FLG mutations (R501X and 2282del4) are responsible for the coexistence of AD, allergic rhinitis, bronchial asthma, single-nucleotide polymorphism SNPs -AD and bronchial asthma, polymorphism rs11204981bronchial asthma [18][19][20].
Focusing on the problem in the pediatric population has shown that there is a lack of studies of the FLG polymorphism role in allergic pathology of children. The few published data report that in children with AD of eastern countries, FLG SCIENTIFIC COLLECTION «INTERCONF» | № 58 191 2282del4 mutation is registered with a frequency of 12.62%. In the pediatric population of Ukrainians, the FLG rs11204981 polymorphism takes place in children with bronchial asthma, with 5% of patients having the minor allele, 27%the heterozygous allele, and 67%the major allele [18,21].
The aim of the study. To determine the role of genetic polymorphism in the filaggrin gene R501XAA and 2282de4AA in atopic march progression in children.

Materials and methods
As a result of screening, 111 children aged 3-12 years old with atopic dermatitis were selected and examined to solve the set tasks.  Fig. 1 The results in Fig. 1   According to the presented results, there was not significant difference between the groups in the spectrum of concomitant pathology, but the children of the main group were diagnosed bronchial asthma more frequently, which can be