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Filaggrin mutations increase allergic airway disease in childhood and adolescence through interactions with eczema and aeroallergen sensitization

Filaggrin mutations increase allergic airway disease in childhood and adolescence through interactions with eczema and aeroallergen sensitization
Filaggrin mutations increase allergic airway disease in childhood and adolescence through interactions with eczema and aeroallergen sensitization

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 < 0.001), 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 = 0.002).

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. This article is protected by copyright. All rights reserved.

Journal Article
0954-7894
147-155
Chan, Adrian
efaa9cf7-300c-4458-9d3d-45dc47ebbe85
Terry, William
cc83c83e-9021-4767-942a-eb9149b70157
Zhang, Hongmei
9f774048-54d6-4321-a252-3887b2c76db0
Karmaus, Wilfried
281d0e53-6b5d-4d38-9732-3981b07cd853
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Holloway, John W
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Roberts, Graham
ea00db4e-84e7-4b39-8273-9b71dbd7e2f3
Kurukulaaratchy, Ramesh
9c7b8105-2892-49f2-8775-54d4961e3e74
Arshad, Syed Hasan
917e246d-2e60-472f-8d30-94b01ef28958
Chan, Adrian
efaa9cf7-300c-4458-9d3d-45dc47ebbe85
Terry, William
cc83c83e-9021-4767-942a-eb9149b70157
Zhang, Hongmei
9f774048-54d6-4321-a252-3887b2c76db0
Karmaus, Wilfried
281d0e53-6b5d-4d38-9732-3981b07cd853
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Holloway, John W
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Roberts, Graham
ea00db4e-84e7-4b39-8273-9b71dbd7e2f3
Kurukulaaratchy, Ramesh
9c7b8105-2892-49f2-8775-54d4961e3e74
Arshad, Syed Hasan
917e246d-2e60-472f-8d30-94b01ef28958

Chan, Adrian, Terry, William, Zhang, Hongmei, Karmaus, Wilfried, Ewart, Susan, Holloway, John W, Roberts, Graham, Kurukulaaratchy, Ramesh and Arshad, Syed Hasan (2018) Filaggrin mutations increase allergic airway disease in childhood and adolescence through interactions with eczema and aeroallergen sensitization. Clinical & Experimental Allergy, 48 (2), 147-155. (doi:10.1111/cea.13077).

Record type: Article

Abstract

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 < 0.001), 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 = 0.002).

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. This article is protected by copyright. All rights reserved.

Text Draft_Filaggrin_Airway_Disease_CEA_submission_Revision 3 Oct 2017 - Accepted Manuscript
Restricted to Repository staff only until 19 December 2018.
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Text Supplementary Table and Figures - Accepted Manuscript
Restricted to Repository staff only until 19 December 2018.
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More information

Accepted/In Press date: 1 December 2017
e-pub ahead of print date: 19 December 2017
Published date: February 2018
Additional Information: This article is protected by copyright. All rights reserved.
Keywords: Journal Article

Identifiers

Local EPrints ID: 416653
URI: https://eprints.soton.ac.uk/id/eprint/416653
ISSN: 0954-7894
PURE UUID: bfa4710d-66c5-4396-8294-5e3b697346d0
ORCID for John W Holloway: ORCID iD orcid.org/0000-0001-9998-0464

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Date deposited: 04 Jan 2018 17:30
Last modified: 04 Aug 2018 00:37

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Contributors

Author: Adrian Chan
Author: William Terry
Author: Hongmei Zhang
Author: Wilfried Karmaus
Author: Susan Ewart
Author: John W Holloway ORCID iD
Author: Graham Roberts
Author: Ramesh Kurukulaaratchy

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