Cansın SAÇKESEN, Bülent Enis ŞEKEREL, Betül BÜYÜKTİRYAKİ, Ebru ARIK YILMAZ, Özlem CAVKAYTAR, Ümit Murat SAHİNER, Neşe VARDAR ACAR, Çağatay KARAASLAN

Rare occurrence of common filaggrin mutations in Turkish children with food allergy and atopic dermatitis

Background/aim: Filaggrin is a protein complex involved in epidermal differentiation and skin barrier formation. Mutations of the filaggrin gene (FLG) are associated with allergen sensitization and allergic diseases like atopic dermatitis (AD), allergic rhinitis, food allergy (FA), and asthma. The aim of the study is to reveal the frequency of change in the FLG gene and determine the association between FLG loss-of-function (LOF) mutations and FA and/or AD in Turkish children. Materials and methods: Four FLG loss-of-function (LOF) mutations known to be common in European populations were analyzed in 128 healthy children, 405 food-allergic children with or without atopic dermatitis, and 61 children with atopic dermatitis. PCRRFLP was performed for genotyping R501X, 2282del4, and R2447X mutations; S3247X was genotyped using a TaqMan-based allelic discrimination assay. Results were confirmed by DNA sequence analysis in 50 randomly chosen patients for all mutations. Results: A total of 466 patients [(67% male, 1 (0.7–2.8) years] and 128 healthy controls [59% male, 2.4 (1.4–3.5) years)] were included in this study. Two patients were heterozygous carriers of wild-type R501X, but none of the controls carried this mutation. Three patients and one healthy control were heterozygous carriers of wild-type 2282del4. Neither patients nor controls carried R2447X or S3247X FLG mutations. There were no combined mutations determined in heterozygous mutation carriers. Conclusions: Although R501X, 2282del4, R2447X, and S3247X mutations are very common in European populations, we found that FLG mutations were infrequent and there is no significant association with food allergy and/or atopic dermatitis in Turkish individuals.

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1. Osawa R, Akiyama M, Shimizu H. Filaggrin gene defects and the risk of developing allergic disorders. Allergology International 2011; 60 (1): 1-9. doi: 10.2332/allergolint.10- RAI-0270
2. Sandilands A, Sutherland C, Irvine AD, McLean WH. Filaggrin in the frontline: role in skin barrier function and disease. Journal of Cell Science 2009; 122 (9): 1285-1294. doi: 10.1242/ jcs.033969
3. Cabanillas B, Novak N. Atopic dermatitis and filaggrin. Current Opinion in Immunology 2016; 42: 1-8. doi: 10.1016/j. coi.2016.05.002
4. Visser MJ, Verberk MM, Campbell LE, McLean WH, Calkoen F et al. Filaggrin loss-of-function mutations and atopic dermatitis as risk factors for hand eczema in apprentice nurses: part II of a prospective cohort study. Contact Dermatitis 2014; 70 (3): 139-150. doi: 10.1111/cod.12139
5. McLean WH. Filaggrin failure - from ichthyosis vulgaris to atopic eczema and beyond. British Journal of Dermatology 2016; 175 (Suppl. 2): 4-7. doi: 10.1111/bjd.14997
6. Cascella R, Strafella C, Germani C, Manzo L, Marsella LT et al. FLG (filaggrin) null mutations and sunlight exposure: Evidence of a correlation. Journal of The American Academy of Dermatology 2015; 73 (3): 528-529. doi: 10.1016/j. jaad.2015.06.022
7. Fallon PG, Sasaki T, Sandilands A, Campbell LE, Saunders SP et al. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nature Genetics 2009; 41 (5): 602-608. doi: 10.1038/ng.358
8. Tan HT, Ellis JA, Koplin JJ, Matheson MC, Gurrin LC et al. Filaggrin loss-of-function mutations do not predict food allergy over and above the risk of food sensitization among infants. Journal of Allergy and Clinical Immunology 2012; 130 (5): 1211-1213. doi: 10.1016/j.jaci.2012.07.022
9. Venkataraman D, Soto-Ramirez N, Kurukulaaratchy RJ, Holloway JW, Karmaus W et al. Filaggrin loss-of-function mutations are associated with food allergy in childhood and adolescence. Journal of Allergy and Clinical Immunology 2014; 134 (4): 876-882. doi: 10.1016/j.jaci.2014.07.033
10. van Ginkel CD, Flokstra-de Blok BM, Kollen BJ, Kukler J, Koppelman GH et al. Loss-of-function variants of the filaggrin gene are associated with clinical reactivity to foods. Allergy 2015; 70 (4): 461-464. doi: 10.1111/all.12569
11. Brown SJ, Asai Y, Cordell HJ, Campbell LE, Zhao Y et al. Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. Journal of Allergy and Clinical Immunology 2011; 127 (3): 661-667. doi: 10.1016/j. jaci.2011.01.031
12. Buyuktiryaki B, Cavkaytar O, Sahiner UM, Yilmaz EA, Yavuz ST et al. Cor a 14, hazelnut-specific IgE, and SPT as a reliable tool in hazelnut allergy diagnosis in eastern Mediterranean children. Journal of Allergy and Clinical Immunology: In Practice 2016; 4 (2): 265-272. doi: 10.1016/j.jaip.2015.12.012
13. Lieberman JA, Sicherer SH. The diagnosis of food allergy. American Journal of Rhinology and Allergy 2010; 24 (6): 439- 443. doi: 10.2500/ajra.2010.24.3515
14. Eichenfield LF, Hanifin JM, Luger TA, Stevens SR, Pride HB. Consensus conference on pediatric atopic dermatitis. Journal of the American Academy of Dermatology 2003; 49 (6): 1088- 1095. doi: 10.1067/S0190
15. Kunz B, Oranje AP, Labreze L, Stalder JF, Ring J et al. Clinical validation and guidelines for the SCORAD index: consensus report of the European Task Force on Atopic Dermatitis. Dermatology 1997; 195 (1): 10-19. doi: 10.1159/000245677
16. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ et al. Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2) LEN and AllerGen). Allergy 2008; 63 (Suppl. 86): 8-160. doi: 10.1111/j.1398-9995.2007.01620.x
17. Reddel HK, Bateman ED, Becker A, Boulet LP, Cruz AA et al. A summary of the New GINA Strategy: A roadmap to asthma control. European Respiratory Journal 2015; 46 (3): 622-639.
18. Poncz M, Solowiejczyk D, Harpel B, Mory Y, Schwartz E et al. Construction of human gene libraries from small amounts of peripheral blood: analysis of beta-like globin genes. Hemoglobin 1982; 6 (1): 27-36. doi: 10.3109/03630268208996930
19. Sandilands A, Terron-Kwiatkowski A, Hull PR, O’Regan GM, Clayton TH et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nature Genetics 2007; 39 (5): 650- 654. doi: 10.1038/ng2020
20. Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nature Genetics 2006; 38 (3): 337-342. doi: 10.1038/ng1743
21. Spergel JM, Paller AS. Atopic dermatitis and the atopic march. Journal of Allergy and Clinical Immunology 2003; 112 (Suppl. 6): 118-127. doi: 10.1016/j.jaci.2003.09.033
22. Brown SJ, McLean WH. One remarkable molecule: filaggrin. Journal of Investigative Dermatology 2012; 132 (3 Pt. 2): 751- 762. doi: 10.1038/jid.2011.393
23. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. The New England Journal of Medicine 2011; 365 (14): 1315-1327. doi: 10.1056/
24. Palmer CN, Ismail T, Lee SP, Terron-Kwiatkowski A, Zhao Y et al. Filaggrin null mutations are associated with increased asthma severity in children and young adults. Journal of Allergy and Clinical Immunology 2007; 120 (1): 64-68. doi: 10.1016/j.jaci.2007.04.001
25. Rodriguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown SJ et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. Journal of Allergy and Clinical Immunology 2009; 123 (6): 1361-1370. doi: 10.1016/j.jaci.2009.03.036
26. Weidinger S, O’Sullivan M, Illig T, Baurecht H, Depner M et al. Filaggrin mutations, atopic eczema, hay fever, and asthma in children. Journal of Allergy and Clinical Immunology 2008; 121 (5): 1203-1209. doi: 10.1016/j.jaci.2008.02.014
27. Poninska J, Samolinski B, Tomaszewska A, Raciborski F, Samel-Kowalik P et al. Filaggrin gene defects are independent risk factors for atopic asthma in a Polish population: a study in ECAP cohort. PloS One 2011; 6 (2): e16933. doi: 10.1371/ journal.pone.0016933
28. Rice NE, Patel BD, Lang IA, Kumari M, Frayling TM et al. Filaggrin gene mutations are associated with asthma and eczema in later life. Journal of Allergy and Clinical Immunology 2008; 122 (4): 834-836. doi: 10.1016/j.jaci.2008.07.027
29. Ziyab AH, Karmaus W, Zhang H, Holloway JW, Steck SE et al. Association of filaggrin variants with asthma and rhinitis: is eczema or allergic sensitization status an effect modifier? International Archives of Allergy and Immunology 2014; 164 (4): 308-318. doi: 10.1159/000365990
30. Brough HA, Simpson A, Makinson K, Hankinson J, Brown S et al. Peanut allergy: effect of environmental peanut exposure in children with filaggrin loss-of-function mutations. Journal of Allergy and Clinical Immunology 2014; 134 (4): 867-875. doi: 10.1016/j.jaci.2014.08.011
31. Peters RL, Dharmage SC, Gurrin LC, Koplin JJ, Ponsonby AL et al. The natural history and clinical predictors of egg allergy in the first 2 years of life: a prospective, population-based cohort study. Journal of Allergy and Clinical Immunology 2014; 133 (2): 485-491. doi: 10.1016/j.jaci.2013.11.032
32. Li K, Oh WJ, Park KY, Kim KH, Seo SJ. FLG mutations in the East Asian atopic dermatitis patients: genetic and clinical implication. Experimental Dermatology 2016; 25 (10): 816- 818. doi: 10.1111/exd.13063
33. Pipinić IS, Varnai VM, Turk R, Breljak D, Kezić S et al. Low frequency of filaggrin null mutations in Croatia and their relation with allergic diseases. International Journal of Immunogenetics 2013; 40 (3): 192-198
34. Cascella R, Foti Cuzzola V, Lepre T, Galli E, Moschese V et al. Full sequencing of the FLG gene in Italian patients with atopic eczema: evidence of new mutations, but lack of an association. Journal of Investigative Dermatology 2011; 131 (4): 982-984. doi: 10.1038/jid.2010.398
35. Mohamed NS, Hashad DI. Filaggrin Gene Polymorphisms in Egyptian Atopic Dermatitis Patients. Journal of the Medical Research Institute 2010; 31: 19-23.
36. Ercan H, Ispir T, Kirac D, Baris S, Ozen A et al. Predictors of atopic dermatitis phenotypes and severity: roles of serum immunoglobulins and filaggrin gene mutation R501X. Allergologia et Immunopathologia 2013; 41 (2): 86-93. doi: 10.1016/j.aller.2012.03.004
37. Odhiambo JA, Williams HC, Clayton TO, Robertson CF, Asher MI et al. Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three. Journal of Allergy and Clinical Immunology 2009; 124 (6): 1251-1258. doi: 10.1016/j. jaci.2009.10.009
38. Muraro A, Werfel T, Hoffmann-Sommergruber K, Roberts G, Beyer K et al. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy 2014; 69 (8): 1008-1025. doi: 10.1111/all.12429
39. Yavuz ST, Sahiner UM, Buyuktiryaki B, Soyer OU, Tuncer A et al. Phenotypes of IgE-mediated food allergy in Turkish children. Allergy and Asthma Proceedings 2011; 32 (6): 47-55. doi: 10.2500/aap.2011.32.3481