Vijverberg S J H, Koster E S, Tavendale R, Leusink M, Koenderman L, Raaijmakers J A M, Postma D S, Koppelman G H, Turner S W, Mukhopadhyay S, Tse S M, Tantisira K G, Hawcutt D B, Francis B, Pirmohamed M, Pino-Yanes M, Eng C, Burchard E G, Palmer C N A, Maitland-van der Zee A H
Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands.
Department of Respiratory Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands.
Clin Exp Allergy. 2015 Jun;45(6):1051-9. doi: 10.1111/cea.12492.
The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS.
We performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5-12 years, USA), the Genes- environment and Mixture in Latino Americans II- study (n = 745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n = 391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed.
Two SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR = 1.22 (P = 0.013) and OR = 1.22 (P = 0.0017), respectively.
A novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.
吸入性糖皮质激素（ICS）的临床反应与多种基因中的单核苷酸多态性（SNP）相关。本研究旨在探讨类固醇途径基因和哮喘易感基因的变异与接受ICS治疗的儿童和青年哮喘加重之间的关系。
我们对三项队列研究进行了荟萃分析：儿童哮喘药物遗传学：具有抗炎作用的药物（n = 357，年龄：4 - 12岁，荷兰）、BREATHE（n = 820，年龄：3 - 22岁，英国）和儿童哮喘基因环境研究（n = 391，年龄：2 - 16岁，英国）。基于在糖皮质激素信号通路中的作用或与哮喘的报道关联，选择了17个基因。使用两个结局参数来反映哮喘加重情况：上一年的住院次数和口服糖皮质激素（OCS）的使用情况。在三个独立的验证队列中对最显著的关联进行了检验；儿童哮喘管理项目（临床试验，n = 172，年龄：5 - 12岁，美国）、拉丁裔美国人基因 - 环境与混合物II研究（n = 745，年龄：8 - 21岁，美国）和肾上腺抑制药物遗传学队列（n = 391，年龄：5 -
