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Filaggrin mutations increase allergic airway disease in childhood and adolescence through interactions with eczema and aeroallergen sensitization
Author(s) -
Chan Adrian,
Terry William,
Zhang Hongmei,
Karmaus Wilfried,
Ewart Susan,
Holloway John W.,
Roberts Graham,
Kurukulaaratchy Ramesh,
Arshad Syed Hasan
Publication year - 2018
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.13077
Subject(s) - filaggrin , aeroallergen , medicine , sensitization , asthma , immunology , atopic dermatitis , atopy , allergy , allergen
Summary Background Filaggrin loss‐of‐function ( FLG ‐ LOF ) mutations are an established genetic cause of eczema. These mutations have subsequently been reported to increase the risk of aeroallergen sensitization and allergic airway disease. However, it is unclear whether FLG variants require both eczema and aeroallergen sensitization to influence airway disease development long‐term outcomes. Objective To examine the effects of FLG ‐ LOF mutations on allergic airway disease outcomes, with eczema and aeroallergen sensitization as intermediate variables, using the Isle of Wight birth cohort. Methods Study participants were evaluated at ages 1, 2, 4, 10 and 18 years to ascertain the development of allergic diseases (eczema, asthma and allergic rhinitis) and aeroallergen sensitization (determined by skin prick tests). FLG ‐ LOF mutations were genotyped in 1150 subjects. To understand the complex associations between FLG mutations, intermediate variables (eczema and aeroallergen sensitization) and airway disease, path analysis was performed. Results There were significant total effects of FLG ‐ LOF mutations on both asthma and allergic rhinitis at all ages as well as on aeroallergen sensitization up till 10 years old. In the filaggrin‐asthma analysis, a direct effect of FLG ‐ LOF mutations was observed on early childhood eczema (age 1 and 2 years) (relative risk ( RR ) 2.01, 95% CI : 1.74‐2.31, P < .001), and all significant indirect pathways on asthma outcomes passed through eczema at these ages. In contrast, for the filaggrin‐rhinitis model, FLG ‐ LOF mutations exerted significant direct effects on early eczema as well as rhinitis at 10 years ( RR 1.99; 95% CI : 1.72‐2.29, P = .002). Conclusion FLG ‐ LOF mutations are a significant risk factor for later childhood asthma and rhinitis. However, the pathway to asthma is only through early childhood eczema while a direct effect was observed for childhood rhinitis.