Adrian Chan1, William Terry2, Hongmei Zhang3, Wilfried Karmaus3, Susan Ewart4, John W Holloway5, Graham Roberts6,7, Ramesh Kurukulaaratchy6,7, Syed Hasan Arshad5,6. 1. Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore City, Singapore. 2. Department of Applied Mathematics and Statistics, Colorado School of Mines, Colorado, SC, USA. 3. Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA. 4. Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA. 5. Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK. 6. David Hide Asthma and Allergy Research Centre, Isle of Wight, UK. 7. Respiratory Biomedical Research Unit, University Hospitals Southampton NHS Foundation Trust, Southampton, UK.
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 < .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.
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.
Authors: R J Kurukulaaratchy; M H Fenn; L M Waterhouse; S M Matthews; S T Holgate; S H Arshad Journal: Clin Exp Allergy Date: 2003-05 Impact factor: 5.018
Authors: J Bousquet; J M Anto; M Wickman; T Keil; R Valenta; T Haahtela; K Lodrup Carlsen; M van Hage; C Akdis; C Bachert; M Akdis; C Auffray; I Annesi-Maesano; C Bindslev-Jensen; A Cambon-Thomsen; K H Carlsen; L Chatzi; F Forastiere; J Garcia-Aymerich; U Gehrig; S Guerra; J Heinrich; G H Koppelman; M L Kowalski; B Lambrecht; C Lupinek; D Maier; E Melén; I Momas; S Palkonen; M Pinart; D Postma; V Siroux; H A Smit; J Sunyer; J Wright; T Zuberbier; S H Arshad; R Nadif; C Thijs; N Andersson; A Asarnoj; N Ballardini; S Ballereau; A Bedbrook; M Benet; A Bergstrom; B Brunekreef; E Burte; M Calderon; G De Carlo; P Demoly; E Eller; M P Fantini; H Hammad; C Hohman; J Just; M Kerkhof; M Kogevinas; I Kull; S Lau; N Lemonnier; M Mommers; M Nawijn; A Neubauer; S Oddie; J Pellet; I Pin; D Porta; Y Saes; I Skrindo; C G Tischer; M Torrent; L von Hertzen Journal: Allergy Date: 2015-07-14 Impact factor: 13.146
Authors: N Lazic; G Roberts; A Custovic; D Belgrave; C M Bishop; J Winn; J A Curtin; S Hasan Arshad; A Simpson Journal: Allergy Date: 2013-04-29 Impact factor: 13.146