Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore City, Singapore.
Department of Applied Mathematics and Statistics, Colorado School of Mines, Colorado, SC, USA.
Clin Exp Allergy. 2018 Feb;48(2):147-155. doi: 10.1111/cea.13077.
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.
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.
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.
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).
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.
丝聚蛋白功能丧失（FLG-LOF）突变是特应性皮炎的既定遗传病因。这些突变随后被报道会增加对气传过敏原致敏和过敏性气道疾病的风险。然而，尚不清楚 FLG 变体是否需要特应性皮炎和气传过敏原致敏这两个中间变量来影响气道疾病的长期结局。
通过 Isle of Wight 出生队列，检查 FLG-LOF 突变对过敏性气道疾病结局的影响，特应性皮炎和气传过敏原致敏作为中间变量。
在 1、2、4、10 和 18 岁时评估研究参与者，以确定过敏性疾病（特应性皮炎、哮喘和过敏性鼻炎）和气传过敏原致敏（通过皮肤点刺试验确定）的发展情况。对 1150 名受试者进行了 FLG-LOF 突变基因分型。为了理解 FLG 突变、中间变量（特应性皮炎和气传过敏原致敏）和气道疾病之间的复杂关联，进行了路径分析。
FLG-LOF 突变对所有年龄的哮喘和过敏性鼻炎以及直至 10 岁的气传过敏原致敏都有显著的总效应。在丝聚蛋白-哮喘分析中，FLG-LOF 突变对婴幼儿期特应性皮炎（1 岁和 2 岁）有直接影响（相对风险（RR）2.01，95%可信区间：1.74-2.31，P<.001），且哮喘结局的所有显著间接途径均通过这些年龄的特应性皮炎。相比之下，对于丝聚蛋白-鼻炎模型，FLG-LOF 突变对 10 岁时的早期特应性皮炎和鼻炎有显著的直接影响（RR 1.99；95%可信区间：1.72-2.29，P=.002）。
FLG-LOF 突变是儿童后期哮喘和鼻炎的重要危险因素。然而，哮喘的发病途径仅通过婴幼儿期特应性皮炎，而儿童期鼻炎则有直接影响。
