Ukrainian Journal of Perinatology and Pediatrics. 2023. 1(93): 45-50; doi 10.15574/PP.2023.93.45
Dytiatkovskyi V. O.
Dnipro State Medical University, Ukraine

For citation: Dytiatkovskyi VO. (2023). Genotype-associated clinical markers of atopic phenotype development in children. Ukrainian Journal of Perinatology and Pediatrics. 1(93): 45-50; doi 10.15574/PP.2023.93.45.
Article received: Dec 20, 2022. Accepted for publication: Mar 13, 2023.

Atopic march (AM) occurs as the linear progression of atopic disorders (AtD) from atopic dermatitis (AD) phenotype to its combinations with other AtD: allergic rhinitis/rhinoconjunctivitis (AR/ARC) and bronchial asthma (BA). Thymic stromal lymphopoietin (TSLP) plays an important role in AtD pathogenesis. Single nucleotide variant (SNV) rs11466749 of the TSLP gene during the last decades showed the controversial roles of A/A, A/G and G/G genotypes in occurrence of the mono- and polyorgan AM phenotypes in children.
Purpose – to determine the associations and risks of AM phenotypes with homozygous or heterozygous SNV rs11466749 genotypes of the TSLP gene in children.
Materials and methods. The study involved 398 children aged 3 to 18 years old: 293 children in the main group and 105 – in the control group. Patients of the main group suffered from AtD in 6 different AM phenotypes: «AD», «AR\ARC», «BA», «AD+AR/ARC», «BA+AR/ARC», «AD+AR/ARC+BA»; patients of the control group suffered from gastrointestinal pathology. Patients of all cohorts were genotyped for genotype variants A/A, A/G and G/G rs11466749 TSLP by the polymerase chain reaction in real time. Pearson’ contingency coefficient (rb), Pearson test (ꭕ²), Fisher’s exact test, odds ratio (OR) with a 95% confidence interval (95% CI) were used for statistical processing of the obtained results. Results at p≤0.05 were considered statistically significant.
Results. The homozygous A/A rs11466749 TSLP genotype was significantly most frequent in phenotypes with mono- or oligoorgan affection «AR/ARC» and polyorgan affection «BA+AR/ARC» and «AD+AR/ARC+BA»: 66,2%, 65.3% and 76.9% respectively (p<0.05). Heterozygous genotype A/G rs11466749 TSLP was the second most significant and frequent: «AR/ARC» – 31.0% (p<0.05), «BA+AR/ARC» – 31.9% (p=0.05-0.1) and «AD+AR/ARC+BA» – 11.5% (p<0.05). Genotype A/A rs11466749 TSLP was significantly associated and increased the development risks of the 3 specified AM phenotypes: «AR/ARC» – rb=0.156, OR=1.92 (95% CI: 1.03-3.58, p<0.05); «BA+AR/ARC» – rb=0.147, OR=1.84 (95% CI: 1.0-3.42, p<0.05); «AD+AR/ARC+BA» – rb=0.212, OR=3.27 (95% CI: 1.22-8.80, p<0.05). Genotype A/G rs11466749 TSLP was reliably associated and had a protective effect on the development of bespoke AM phenotypes: «AR/ARC» – rb=0.148, OR=0.53 (95% CI: 0.28-1.0, p<0.05); «BA+AR/ARC2 – rb=0.138, OR=0.55 (95% CI: 0.30-1.04, p=0.05-0.1); «AD+AR/ARC+BA» – rb=0.280, OR=0.15 (95% CI: 0.04-0.55, p<0.05).
Conclusions. The homozygous genotype A/A SNV rs11466749 of TSLP gene significantly increases the risk of developing AM phenotypes «AR/ARC», «BA+AR/ARC» and «AD+AR/ARC+BA», and the heterozygous genotype A/G SNV rs11466749 of TSLP gene possesses a significantly protective effect on their development in children.
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 participating institution. The informed consent of the patient was obtained for conducting the studies.
No conflict of interests was declared by the author.
Keywords: children, genotypes, thymic stromal lymphopoietin, atopic march, phenotypes.
REFERENCES

1. 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

2. Chang J, Mitra N, Hoffstad O, Margolis DJ. (2017, Mar 1). Association of Filaggrin Loss of Function and Thymic Stromal Lymphopoietin Variation With Treatment Use in Pediatric Atopic Dermatitis. JAMA Dermatol. 153 (3): 275-281. https://doi.org/10.1001/jamadermatol.2016.4467; PMid:27902816

3. 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

4. Ebina-Shibuya R, Leonard WJ. (2023, Jan). Role of thymic stromal lymphopoietin in allergy and beyond. Nat Rev Immunol. 23 (1): 24-37. https://doi.org/10.1038/s41577-022-00735-y; PMid:35650271 PMCid:PMC9157039

5. Han H, Thelen TD, Comeau MR, Ziegler SF. (2014, Dec). Thymic stromal lymphopoietin-mediated epicutaneous inflammation promotes acute diarrhea and anaphylaxis. J Clin Invest. 124 (12): 5442-5452. https://doi.org/10.1172/JCI77798; PMid:25365222 PMCid:PMC4348967

6. Harada M, Hirota T, Jodo AI, Doi S, Kameda M, Fujita K et al. (2009, Mar). Functional analysis of the thymic stromal lymphopoietin variants in human bronchial epithelial cells. Am J Respir Cell Mol Biol. 40 (3): 368-374. https://doi.org/10.1165/rcmb.2008-0041OC; PMid:18787178

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

8. Hirota T, Nakayama T, Sato S, Yanagida N, Matsui T, Sugiura S et al. (2017, Dec). Association study of childhood food allergy with genome-wide association studies-discovered loci of atopic dermatitis and eosinophilic esophagitis. J Allergy Clin Immunol. 140 (6): 1713-1716. https://doi.org/10.1016/j.jaci.2017.05.034; PMid:28629743

9. Kabata H, Flamar AL, Mahlakõiv T, Moriyama S, Rodewald HR, Ziegler SF, Artis D. (2020, Jul). Targeted deletion of the TSLP receptor reveals cellular mechanisms that promote type 2 airway inflammation. Mucosal Immunol. 13 (4): 626-636. https://doi.org/10.1038/s41385-020-0266-x; PMid:32066836 PMCid:PMC7311324

10. Khan SJ, Dharmage SC, Matheson MC, Gurrin LC. (2018, Jan). Is the atopic march related to confounding by genetics and early-life environment? A systematic review of sibship and twin data. Allergy. 73 (1): 17-28. https://doi.org/10.1111/all.13228; PMid:28618023

11. Lin SC, Cheng FY, Liu JJ, Ye YL. (2018, Apr 18). Expression and Regulation of Thymic Stromal Lymphopoietin and Thymic Stromal Lymphopoietin Receptor Heterocomplex in the Innate-Adaptive Immunity of Pediatric Asthma. Int J Mol Sci. 19 (4): 1231. https://doi.org/10.3390/ijms19041231; PMid:29670037 PMCid:PMC5979588

12. Malinczak CA et al. (2021). TSLP-driven chromatin remodeling and trained systemic immunity after neonatal respiratory viral infection. J. Immunol. 206: 1315-1328. https://doi.org/10.4049/jimmunol.2001205; PMid:33514510

13. Miyake Y, Hitsumoto S, Tanaka K, Arakawa M. (2015, Aug). Association Between TSLP Polymorphisms and Eczema in Japanese Women: the Kyushu Okinawa Maternal and Child Health Study. Inflammation. 38 (4): 1663-1668. https://doi.org/10.1007/s10753-015-0143-z; PMid:25700684

14. Moorehead A, Hanna R, Heroux D, Neighbour H, Sandford A, Gauvreau GM et al. (2020, Apr). A thymic stromal lymphopoietin polymorphism may provide protection from asthma by altering gene expression. Clin Exp Allergy. 50 (4): 471-478. https://doi.org/10.1111/cea.13568; PMid:31943442

15. Murrison LB, Ren X, Preusse K, He H, Kroner J, Chen X et al. (2022, Jan). TSLP disease-associated genetic variants combined with airway TSLP expression influence asthma risk. J Allergy Clin Immunol. 149 (1): 79-88. https://doi.org/10.1016/j.jaci.2021.05.033; PMid:34111451 PMCid:PMC9119142

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. Ullemar V, Magnusson PK, Lundholm C, Zettergren A, Melén E, Lichtenstein P, Almqvist C. (2016, Feb). Heritability and confirmation of genetic association studies for childhood asthma in twins. Allergy. 71 (2): 230-238. https://doi.org/10.1111/all.12783; PMid:26786172

18. Uller L, Persson C. (2018, Aug). Viral induced overproduction of epithelial TSLP: Role in exacerbations of asthma and COPD? J Allergy Clin Immunol. 142 (2): 712. https://doi.org/10.1016/j.jaci.2018.01.051; PMid:29628119

19. Wang IJ, Wu LS, Lockett GA, Karmaus WJ. (2016, Feb). TSLP polymorphisms, allergen exposures, and the risk of atopic disorders in children. Ann Allergy Asthma Immunol. 116 (2): 139-145.e1. Epub 2015 Dec 18. https://doi.org/10.1016/j.anai.2015.11.016; PMid:26712523

20. Ziegler SF. (2021, Sep). Thymic stromal lymphopoietin, skin barrier dysfunction, and the atopic march. Ann Allergy Asthma Immunol. 127 (3): 306-311. https://doi.org/10.1016/j.anai.2021.06.004; PMid:34153443 PMCid:PMC8419079