Lack of Association Between Toll-like Receptor 2 Polymorphisms (R753Q and A-16934T) and Atopic Dermatitis in Children from Thrace Region of Turkey

Abstract

Background: Atopic dermatitis is the most common chronic inflammatory skin disease. A complex interaction of both genetic and environmental factors is thought to contribute to the disease. Aims: To evaluate whether single nucleotide polymorphisms in the TLR2 gene c.2258C>T (R753Q) (rs5743708) and TLR2 c.-148+1614T>A (A-16934T) (rs4696480) (NM_0032643) are associated with atopic dermatitis in Turkish children. Study Design: Case-control study. Methods: The study was conducted on 70 Turkish children with atopic dermatitis aged 0.5-18 years. The clinical severity of atopic dermatitis was evaluated by the severity scoring of atopic dermatitis index. Serum total IgE levels, specific IgE antibodies to inhalant and food allergens were measured in both atopic dermatitis patients and controls, skin prick tests were done on 70 children with atopic dermatitis. Genotyping for TLR2 (R753Q and A-16934T) single nucleotide polymorphisms was performed in both atopic dermatitis patients and controls. Results: Cytosine-cytosine and cytosin-thymine genotype frequencies of the TLR2 R753Q single nucleotide polymorphism in the atopic dermatitis group were determined as being 98.6% and 1.4%, cytosine allele frequency for TLR2 R753Q single nucleotide polymorphism was determined as 99.29% and the thymine allele frequency was 0.71%, thymine-thymine, thymine-adenine, and adenine-adenine genotype frequencies of the TLR2 A-16934T single nucleotide polymorphism were 24.3%, 44.3%, and 31.4%. The thymine allele frequency for the TLR2 A-16934T single nucleotide polymorphism in the atopic dermatitis group was 46.43%, and the adenine allele frequency was 53.57%, respectively. There was not statistically significant difference between the groups for all investigated polymorphisms (p>0.05). For all single nucleotide polymorphisms studied, allelic distribution was analogous among atopic dermatitis patients and controls, and no significant statistical difference was observed. No homozygous carriers of the TLR2 R753Q single nucleotide polymorphism were found in the atopic dermatitis and control groups. Conclusion: The TLR2 (R753Q and A-16934T) single nucleotide polymorphisms are not associated with atopic dermatitis in a group of Turkish patients.

Keywords

• Allergy, atopic dermatitis, polymorphism, toll-like receptor

Kaynakça

1. 1. Asher MI, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland SK, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 2006;368:733-43.
2. 2. Wuthrich B, Cozzio A, Roll A, Senti G, Kundig T, Schmid-Grendelmeier P. Atopic eczema: genetics or environment? Ann Agric Environ Med 2007;14:195-201.
3. 3. Bieber T. Atopic dermatitis. Ann Dermatol 2010;22:125-37.
4. 4. Lyons JJ, Milner JD, Stone KD. Atopic dermatitis in children: clinical features, pathophysiology, and treatment. Immunol Allergy Clin North Am 2015;35:161-83.
5. 5. Niebuhr M, Langnickel J, Draing C, Renz H, Kapp A, Werfel T. Dysregulation of toll-like receptor-2 (TLR-2)-induced effects in monocytes from patients with atopic dermatitis: impact of the TLR-2 R753Q polymorphism. Allergy 2008;63:728-34.
6. 6. Mrabet-Dahbi S, Dalpke AH, Niebuhr M, Frey M, Draing C, Brand S, et al. The Toll-like receptor 2 R753Q mutation modifies cytokine production and Toll-like receptor expression in atopic dermatitis. J Allergy Clin Immunol 2008;121:1013-9.
7. 7. Salpietro C, Rigoli L, Miraglia Del Giudice M, Cuppari C, Di Bella C, Salpietro A, et al. TLR2 and TLR4 gene polymorphisms and atopic dermatitis in Italian children: a multicenter study. Int J Immunopathol Pharmacol 2011;24(4 Suppl):33-40.
8. 8. Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002;20:197-216

9. 9. Napolitani G, Rinaldi A, Bertoni F, Sallusto F, Lanzavecchia A. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol 2005;6:769-76.
10. 10. Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest 2004;113:651-7.
11. 11. Aliprantis AO, Yang RB, Mark MR, Suggett S, Devaux B, Radolf JD, et al. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 1999;285:736-9.
12. 12. Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 1999;11:443-51.
13. 13. McGirt LY, Beck LA. Innate immune defects in atopic dermatitis. J Allergy Clin Immunol 2006;118:202-8.
14. 14. Yu YY, Yip KH, Tam IYS, Sam SW, Ng CW, Lau HYA. Differential effects of the Toll-like receptor 2 agonists, PGN and Pam3CSK4 on substance P induced human mast cell activation. Eur J Inflamm. 2013;3:709-18.
15. 15. Yu Y, Zhang Y, Zhang J, Dou X, Yang H, Shao Y, et al. Impaired Tolllike receptor 2-mediated Th1 and Th17/22 cytokines secretion in human peripheral blood mononuclear cells from patients with atopic dermatitis. J Transl Med 2015;13:384.
16. 16. Oh DY, Schumann RR, Hamann L, Neumann K, Worm M, Heine G. Association of the toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitis. Allergy 2009;64:1608-15.
17. 17. Ahmad-Nejad P, Mrabet-Dahbi S, Breuer K, Klotz M, Werfel T, Herz U, et al. The toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype. J Allergy Clin Immunol 2004;113:565-7.
18. 18. Potaczek DP, Nastalek M, Okumura K, Wojas-Pelc A, Undas A, Nishiyama C. An association of TLR2–16934A >T polymorphism and severity/phenotype of atopic dermatitis. J Eur Acad Dermatol Venereol 2011;25:715-21.
19. 19. Levchenko LIu, Izmaĭlova OV, Shlykova OA, Kaĭdashev IP. Polymorphism 896A/G of TLR4 gene rather than 1196C/T and 2258G/A of TLR2 gene determines severe and complicated course of atopic dermatitis in children. Tsitol Genet 2013;47:46-53.
20. 20. Novak N, Yu CF, Bussmann C, Maintz L, Peng WM, Hart J, et al. Putative association of a TLR9 promoter polymorphism with atopic eczema. Allergy 2007;62:766-72.
21. 21. Schimming TT, Parwez Q, Petrasch-Parwez E, Nothnagel M, Epplen JT, Hoffjan S. Association of toll-interacting protein gene polymorphisms with atopic dermatitis. BMC Dermatol 2007;7:3.
22. 22. Beygo J, Parwez Q, Petrasch-Parwez E, Epplen JT, Hoffjan S. No evidence of an association between polymorphisms in the IRAK-M gene and atopic dermatitis in a German cohort. Mol Cell Probes 2009;23:16-9.
23. 23. Miller LS. Toll-like receptors in skin. Adv Dermatol 2008;24:71-87.
24. 24. Akdis CA, Akdis M, Bieber T, Bindslev-Jensen C, Boguniewicz M, Eigenmann P, et al. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/ American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. Allergy 2006;61:969-87.
25. 25. No authors listed. Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology 1993;186:23-31.
26. 26. Eder W, Klimecki W, Yu L, von Mutius E, Riedler J, Braun-Fahrländer C, et al. Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol 2004;113:482-8.
27. 27. Kormann MS, Ferstl R, Depner M, Klopp N, Spiller S, Illig T, et al. Rare TLR2 mutations reduce TLR2 receptor function and can increase atopy risk. Allergy 2009;64:636-42.
28. 28. Weidinger S, Novak N, Klopp N, Baurecht H, Wagenpfeil S, Rummler L, et al. Lack of association between Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and atopic eczema. J Allergy Clin Immunol 2006;118:277- 9.
29. 29. Smit LA, Bongers SI, Ruven HJ, Rijkers GT, Wouters IM, Heederik D, et al. Atopy and new-onset asthma in young Danish farmers and CD14, TLR2, and TLR4 genetic polymorphisms: a nested case-control study. Clin Exp Allergy 2007;37:1602-8.
30. 30. Galli E, Ciucci A, Cersosimo S, Pagnini C, Avitabile S, Mancino G, et al. Eczema and food allergy in an Italian pediatric cohort: no association with TLR-2 and TLR-4 polymorphisms. Int J Immunopathol Pharmacol 2010;23:671-5.