The role of filaggrin mutations leading to a decrease in the amount of protein in the development of atopic dermatitis and bronchial asthma in children

Atopic diseases remain one of the most common childhood diseases. At the beginning of life, atopic dermatitis (AD) occurs, and only then bronchial asthma (BA). This staged development of sensitization and transformation of clinical manifestations is called the atopic march. Are the genetic factors of predisposition to AD the same for BA? There is still no definite answer to this question. Mutations in the filaggrin gene (FLG) are known to impair skin barrier function. Filaggrin is expressed not only in the skin, but also in the respiratory organs of the nasal mucosa, lungs, and bronchi. Filaggrin defects lead not only to disruption of the skin barrier, but also to an increase in the Th2 response and increased production of IgE, typical of bronchial asthma. Therefore, mutations in the FLG gene can be a risk factor for the development of not only AD, but also BA.

The aim of this study was to compare the values of the association of mutations in the FLG gene with AD and BA in the Russian sample.

Material and methods. Case-control study design. We used 265 blood samples from children. 4 mutations in the filaggrin gene were identified by real-time PCR. The association of mutations with disease was assessed by odds ratio.

Results. We showed a strongly pronounced association of the deletion of 4 nucleotides (2282del4) with AD, but not with BA, although for patients with atopic BA the indicator of the association of this mutation with the disease was higher than for the group with symptoms of bronchial asthma identified by the ISAAC questionnaire. These results lead to the conclusion that the role of the filaggrin gene for BA is much less significant than for AD.

1. Kubanova A.A., Kubanov A.A., Melekhina L.E., Bogdanova E.V. Analysis of the incidence of diseases of the skin and subcutaneous tissue in the Russian Federation for the period 2003-2016. Vestnik dermatologii i venerologii = Dermatology and Venereology Bulletin. 2017; (6): 22-33. [In Russian]. https://doi.org/0.25208/0042-4609-2017-93-6-22-33

2. Ksenzova L.D Atopic march. Risk of developing of allegic rhinitis and bronchial asthma in children with atopic dermatitis. Allergologiya i immunologiya v pediatrii = Allergology and Immunology in Paediatrics. 2018; 55 (4): 25-30. [In Russian]. https://doi.org/10.24411/2500-1175-2018-0019

3. Paller A.S., Spergel J.M., Mina-Osorio P., Irvine A.D. The atopic march and atopic multimorbidity: Many trajectories, many pathways. J. Allergy Clin. Immunol. 2019: 143 (1): 46-55. https://doi.org/10.1016/j.jaci.2018.11.006

4. Chan A., Terry W., Zhang H., Karmaus W., Ewart S., Holloway J.W., Roberts G., Kurukulaaratchy R., Arshad S.H. Filaggrin mutations increase allergic airway disease in childhood and adolescence through interactions with eczema and aeroallergen sensitization. Clin. Exp. Allergy. 2018; 48 (2): 147-155. https://doi.org/10.1111/cea.13077

5. FLG Gene (Protein Coding). Available at: https://www.genecards.org/cgibin/carddisp.pl?gene=FLG&k eywords=FLG#expression

6. Aw M., Penn J., Gauvreau G.M., Lima H., Sehmi R. Atopic march: Collegium Internationale Aller-gologicum Update 2020. Int. Arch. Allergy Immunol. 2020; 181 (1): 1-10. https://doi.org/10.1159/000502958

7. Dębińska A., Danielewicz H., Drabik-Chamerska A., Kalita D., Boznański A. Filaggrin loss-of-function mutations as a predictor for atopic eczema, allergic sensitization and eczema-associated asthma in Polish children population. Adv. Clin. Exp. Med. 2017: 26 (6): 991-998. https://doi.org/10.17219/acem/61430

8. Salikova T.I., Maksimov V.N., Maksimova Yu.V., Allakhverdyan A.A., Klimov V.V., Denisov A.A., Koshovkina T.V. Mutations in the filaggrin gene as a predisposing factor in the development of atopic dermatitis. Klinicheskaya dermatologiya i venerologiya = The Russian Journal of Dermatology and Venereology. 2010; 8 (3): 4-7. [In Russian].

9. Komova E.G., Shintyapina A.B., Makarova S.I., Ivanov M.K., Chekryga E.A., Kaznacheeva L.F., Vavilin V.A. Filaggrin mutations in a Western siberian population and their association with atopic dermatitis in children. Genet. Test. Mol. Biomarkers. 2014; 18 (12): 791-796. https://doi.org/10.1089/gtmb.2014.0247

10. Gimalova G.F., Karunas A.S., Fedorova Y.Y., Khusnutdinova E.K. The study of filaggrin gene mutations and copy number variation in atopic dermatitis patients from Volga-Ural region of Russia. Gene. 2016; 591 (1): 85-89. https://doi.org/10.1016/j.gene.2016.06.054

11. Maksimov V.N., Kulikov I.V., Semaev S.E., Maksimova Yu.V., Prostyakova E.M., Malyutina S.K., Ro-mashchenko A.G., Voevoda M.I. Deletion of 2282del4 in the filaggrin gene in the population of residents of Novosibirsk and in patients with vulgar ichthyosis. Meditsinskaya genetika = Medical Genetics. 2007; 6 (8): 21-24. [In Russian].

12. Prasolova M.A., Shchepotina E.G., Dymshits G.M. Development of a high-throughput fluorescence assay for detecting SNPs in hemostasis and folate metabolism genes for clinical use. Molecular Genetics, Microbiology and Virology. 2013; (1): 24-31. https://doi.org/10.3103/S0891416813010047

13. Pividori M., Schoettler N., Nicolae D.L., Ober C., Im H.K. Shared and distinct genetic risk factors for childhood-onset and adult-onset asthma: genome-wide and transcriptome-wide studies. Lancet. Respir. Med. 2019; 7 (6): 509-522. https://doi.org/10.1016/S2213-2600(19)30055-4

14. Irvine A.D., McLean W.H., Leung D.Y Filaggrin mutations associated with skin and allergic diseases. N. Engl. J. Med. 2011; 365 (14): 1315-1327. https://doi.org/10.1056/NEJMra1011040

15. Petersen T.H., Jee M.H., Gadsb0ll A.0., Schmidt J.D., Sloth J.J., Sonnenberg G.F., Geisler C., Thyssen J.P., Bonefeld C.M. Mice with epidermal fil-aggrin deficiency show increased immune reactivity to nickel. Contact dermatitis. 2019; 80 (3): 139-148. https://doi.org/10.1111/cod.13153

16. Belgrave D.C., Granell R., Simpson A., Gui-ver J., Bishop C., Buchan I., Henderson A.J., Custovic A. Developmental profiles of eczema, wheeze, and rhinitis: two population-based birth cohort studies. PLoS Med. 2014; 11 (10): e1001748. https://doi.org/10.1371/journal.pmed.1001748