Modern Pediatrics. Ukraine. (2023). 6(134): 98-104. doi 10.15574/SP.2023.134.98
Dytiatkovskyi  V. O.
Dnipro State Medical University, Ukraine

For citation: Dytiatkovskyi VO. (2023). Association of bronchial asthma phenotypes in children with single-nucleotide variants of filaggrin, thymic stromal lymphopoietin and orsomucoid-1-like protein 3 genes. Modern Pediatrics. Ukraine. 6(134): 98-104. doi 10.15574/SP.2023.134.98.
Article received: Jul 22, 2023. Accepted for publication: Oct 10, 2023.

Bronchial asthma (BA) composes the most severe form of atopic march (AM) in children, which also includes atopic dermatitis (AD),allergic rhinitis and rhino-conjunctivitis (AR/ARC). AM can clinically manifest as mono-organ phenotypes of AD, AR/AR and BA or poly-organ phenotypes of AD+AR/ARC, BA+AR/ARC, AD+AR/ARC+BA. Single nucleotide variants (SNVs) of genes: rs_7927894 of filaggrin (FLG), rs_11466749 of thymic stromal lymphopoietin (TSLP) and rs_7216389 of orsomucoid-1-like protein 3 (ORMDL3) are important factors in the development of AM in children.
The aim was to study the role of different variants of rs_7927894 FLG, rs_11466749 TSLP and rs_7216389 ORMDL3 genotypes in the risks of AM – BA, BA+AR/ARC and AD+AR/ARC+BA phenotypes` development.
Materials and methods. 121 children of the main group and 105 of the control group aged from 3 to 18 years were involved in the study. Cohorts of the main group: BA – 23 children, BA+AR/ARC – 72 children, AD+AR/ARC+BA – 26 children. The control group consisted of 105 children without AM nosoloies. All children were genotyped by polymerase chain reaction in real time for SNVs C/T, C/C T/T rs_7927894 FLG, A/A, A/G, G/G rs_11466749 TSLP and C/C, C/T, T/T rs_7216389 ORMDL3. For the statistical processing of the obtained results, the methods of variational statistics were applied with the statistical significance threshold at the value of p<0.05, trend to significance – p=0.05-0.1.
Results. AD+AR/ARC+BA correlated to BA+AR/ARC: A/G rs_11466749 – reduces the risk, r=0.204, odds ratio (OR)=0.28 (0.08-1.0, p<0.05); T/T rs_7216389 – reduces the risk, r=0.172, OR=0.40 (0.13-1.17, p=0.09). AD+AR/ARC+BA correlated to BA: A/A rs_11466749 – elevates the risk, r=0.259, OR=3.06 (0.9-10.4, p=0.07), A/G rs_11466749 – reduces the risk, r=0.320, OR=0.20 (0.05-0.88, p<0.05).
Conclusions. SNV C/T rs_7927894 FLG, A/A rs_11466749 TSLP and T/T rs_7216389 ORMDL3 are associated and elevate the risk of BA+AR/ARC phenotype by 1.87, 1.84 and 3.34 fold, and C/C rs_7216389 ORMDL3 and A/G rs_11466749 TSLP reduce it to 0.42 and 0.56 times. SNV C/T rs_7927894 FLG and A/A rs_11466749 TSLP are associated and increase the risk of developing the full AM AD+AR/ARC+BA phenotype by 3.34 and 3.27fold, and C/C rs_7927894 FLG and A/G rs_11466749 TSLP – are associated and reduce it by 0.45 and 0.15 fold. SNV A/A rs_11466749 TSLP is associated with an elevated risk of developing AD+AR/ARC+BA correlated to BA up to 3.06 fold, and SNV A/G rs_11466749 TSLP is associated and reduces it by 0.20 fold. SNV A/G rs_11466749 TSLP and T/T rs_7216389 ORMDL3 are associated and reduce the risk of AD+AR/ARC+BA phenotype development correlated to BA+AR/ARC by 0.28 and 0.40 fold, respectively.
The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the institution mentioned in the work. The informed consent of the parents and  the children was obtained for the conducting the study.
No conflict of interests was declared by the author.
Keywords: atopic march, children, bronchial asthma, poly-organ phenotype, mono-organ phenotype, single-nucleotide variants.

REFERENCES

1. Acevedo N, Reinius LE, Greco D, Gref A, Orsmark-Pietras C, Persson H et al. (2015, Feb 1). Risk of childhood asthma is associated with CpG-site polymorphisms, regional DNA methylation and mRNA levels at the GSDMB/ORMDL3 locus. Hum Mol Genet. 24 (3): 875-890. https://doi.org/10.1093/hmg/ddu479; PMid:25256354 PMCid:PMC4291244

2. Andiappan AK, Sio YY, Lee B, Suri BK, Matta SA, Lum J et al. (2016, Mar). Functional variants of 17q12-21 are associated with allergic asthma but not allergic rhinitis. J Allergy Clin Immunol. 137 (3): 758-766.e3. https://doi.org/10.1016/j.jaci.2015.08.038; PMid:26483175

3. Birben E, Sahiner UM, Karaaslan C, Yavuz TS, Cosgun E, Kalayci O, Sackesen C. (2014). The genetic variants of thymic stromal lymphopoietin protein in children with asthma and allergic rhinitis. Int Arch Allergy Immunol. 163 (3): 185-192. https://doi.org/10.1159/000358488; PMid:24525665

4. Bønnelykke K, Pipper CB, Tavendale R, Palmer CN, Bisgaard H. (2010, Sep). Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth. Pediatr Allergy Immunol. 21 (6): 954-961. https://doi.org/10.1111/j.1399-3038.2010.01073.x; PMid:20573035

5. Bønnelykke K, Pipper CB, Tavendale R, Palmer CN, Bisgaard H. (2010, Sep). Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth. Pediatr Allergy Immunol. 21 (6): 954-961. https://doi.org/10.1111/j.1399-3038.2010.01073.x; PMid:20573035

6. Čepelak I, Dodig S, Pavić I. (2019, Jun 15). Filaggrin and atopic march. Biochem Med (Zagreb). 29 (2): 020501. https://doi.org/10.11613/BM.2019.020501; PMid:31223255 PMCid:PMC6559618

7. Dytiatkovskyi VO, Naumenko NV, Alifirenko OO ta in. (2022). Odnonukleotydni varianty heniv filahrinu ta hliukokrotykoidnykh retseptoriv u ditei, khvorykh na rizni fenotypy atopichnykh zakhvoriuvan. Medychni perspektyvy. 27; 1: 132-139. https://doi.org/10.26641/2307-0404.2022.1.254378

8. Dytiatkovskyi VO. (2021). Role of single nucleotide variants of thymic stromal lymphopoietin in the mono- and polyorganic lesions within atopic disorders in children Modern Pediatrics. Ukraine. 8 (120): 23-29. https://doi.org/10.15574/SP.2021.120.23

9. Dytiatkovskyi VO. (2023). Asotsiatsiia odnonukleotydnykh variantiv hena orsomukoid-1-podibnoho bilka 3 z fenotypamy atopichnoho marshu v ditei. Zdorov'ia dytyny. 3 (18): 52-58. https://doi.org/10.22141/2224-0551.18.3.2023.1586

10. Gautam Y, Afanador Y, Ghandikota S, Mersha TB. (2020, Aug). Comprehensive functional annotation of susceptibility variants associated with asthma. Hum Genet. 139 (8): 1037-1053. https://doi.org/10.1007/s00439-020-02151-5; PMid:32240371 PMCid:PMC7415519

11. Harada M, Hirota T, Jodo AI, Hitomi Y, Sakashita M, Tsunoda T et al. (2011, Jun). Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma. Am J Respir Cell Mol Biol. 44 (6): 787-793. https://doi.org/10.1165/rcmb.2009-0418OC; PMid:20656951 PMCid:PMC3159073

12. Hill DA, Spergel JM. (2018). The atopic march. Ann Allergy Asthma Immuno. 120 (2): 131-137. https://doi.org/10.1016/j.anai.2017.10.037; PMid:29413336 PMCid:PMC5806141

13. Kreiner-Møller E, Strachan DP, Linneberg A, Husemoen LL, Bisgaard H, Bønnelykke K. (2015, Jan). 17q21 gene variation is not associated with asthma in adulthood. Allergy. 70 (1): 107-114. https://doi.org/10.1111/all.12537; PMid:25331618

14. Lizzo JM, Cortes S. (2023, Jan). Pediatric Asthma. [Updated 2023 May 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; URL: https://www.ncbi.nlm.nih.gov/books/NBK551631.

15. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S et al. (2007). Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature. 448: 470-473. https://doi.org/10.1038/nature06014; PMid:17611496

16. Ntontsi P, Photiades A, Zervas E, Xanthou G, Samitas K. (2021, Feb 27). Genetics and Epigenetics in Asthma. Int J Mol Sci. 22 (5): 2412. https://doi.org/10.3390/ijms22052412; PMid:33673725 PMCid:PMC7957649

17. Schedel M, Michel S, Gaertner VD, Toncheva AA, Depner M, Binia A et al. (2015, Oct). Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels. J Allergy Clin Immunol. 136 (4): 893-903.e14. https://doi.org/10.1016/j.jaci.2015.03.014; PMid:25930191

18. Thomsen AF (ed.). (2014). Asthma. In: Thyssen JP, Maibach HI eds. Filaggrin. Basic Science, Epidemiology, Clinical Aspects and Management. Heidelberg, New York, Dordrecht, London: Springer: 169-181. https://doi.org/10.1007/978-3-642-54379-1

19. Zhu Z, Lee PH, Chaffin MD, Chung W, Loh PR, Lu Q et al. (2018). A genome-wide cross-trait analysis from UK Biobank highlights the shared genetic architecture of asthma and allergic diseases. Nat Genet. 50 (6): 857-864. https://doi.org/10.1038/s41588-018-0121-0; PMid:29785011 PMCid:PMC5980765