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These mutations have subsequently been reported to increase the risk of aeroallergen sensitization and allergic airway disease. However, it is unclear whether <jats:italic><jats:styled-content style=\"fixed-case\">FLG<\/jats:styled-content><\/jats:italic> variants require both eczema and aeroallergen sensitization to influence airway disease development long\u2010term outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To examine the effects of <jats:italic><jats:styled-content style=\"fixed-case\">FLG<\/jats:styled-content><\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">LOF<\/jats:styled-content> mutations on allergic airway disease outcomes, with eczema and aeroallergen sensitization as intermediate variables, using the Isle of Wight birth cohort.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Study participants were evaluated at ages 1, 2, 4, 10 and 18\u00a0years to ascertain the development of allergic diseases (eczema, asthma and allergic rhinitis) and aeroallergen sensitization (determined by skin prick tests). <jats:italic><jats:styled-content style=\"fixed-case\">FLG<\/jats:styled-content><\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">LOF<\/jats:styled-content> mutations were genotyped in 1150 subjects. To understand the complex associations between <jats:italic><jats:styled-content style=\"fixed-case\">FLG<\/jats:styled-content><\/jats:italic> mutations, intermediate variables (eczema and aeroallergen sensitization) and airway disease, path analysis was performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>There were significant total effects of <jats:italic><jats:styled-content style=\"fixed-case\">FLG<\/jats:styled-content><\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">LOF<\/jats:styled-content> mutations on both asthma and allergic rhinitis at all ages as well as on aeroallergen sensitization up till 10\u00a0years old. In the filaggrin\u2010asthma analysis, a direct effect of <jats:italic><jats:styled-content style=\"fixed-case\">FLG<\/jats:styled-content><\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">LOF<\/jats:styled-content> mutations was observed on early childhood eczema (age 1 and 2\u00a0years) (relative risk (<jats:styled-content style=\"fixed-case\">RR<\/jats:styled-content>) 2.01, 95% <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>: 1.74\u20102.31, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.001), and all significant indirect pathways on asthma outcomes passed through eczema at these ages. In contrast, for the filaggrin\u2010rhinitis model, <jats:italic><jats:styled-content style=\"fixed-case\">FLG<\/jats:styled-content><\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">LOF<\/jats:styled-content> mutations exerted significant direct effects on early eczema as well as rhinitis at 10\u00a0years (<jats:styled-content style=\"fixed-case\">RR<\/jats:styled-content> 1.99; 95% <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>: 1.72\u20102.29, <jats:italic>P<\/jats:italic>\u00a0=\u00a0.002).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic><jats:styled-content style=\"fixed-case\">FLG<\/jats:styled-content><\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">LOF<\/jats:styled-content> 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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cea.13077","type":"journal-article","created":{"date-parts":[[2017,12,20]],"date-time":"2017-12-20T01:22:44Z","timestamp":1513732964000},"page":"147-155","source":"Crossref","is-referenced-by-count":26,"title":["Filaggrin mutations increase allergic airway disease in childhood and adolescence through interactions with eczema and aeroallergen sensitization"],"prefix":"10.1111","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6892-984X","authenticated-orcid":false,"given":"Adrian","family":"Chan","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine Singapore General Hospital Singapore City Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Terry","sequence":"additional","affiliation":[{"name":"Department of Applied Mathematics and Statistics Colorado School of Mines Colorado SC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3557-0364","authenticated-orcid":false,"given":"Hongmei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Biostatistics, and Environmental Health School of Public Health University of Memphis Memphis TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilfried","family":"Karmaus","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Biostatistics, and Environmental Health School of Public Health University of Memphis Memphis TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Ewart","sequence":"additional","affiliation":[{"name":"Department of Large Animal Clinical Sciences Michigan State University East Lansing MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John 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