Accordini Simone, Calciano Lucia, Bombieri Cristina, Malerba Giovanni, Belpinati Francesca, Lo Presti Anna Rita, Baldan Alessandro, Ferrari Marcello, Perbellini Luigi, de Marco Roberto
Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
Section of Biology and Genetics, Department of Neurological, Biomedical and Movement Sciences, University of Verona, Verona, Italy.
PLoS One. 2016 Mar 17;11(3):e0151292. doi: 10.1371/journal.pone.0151292. eCollection 2016.
Different genes are associated with categorical classifications of asthma severity. However, continuous outcomes should be used to catch the heterogeneity of asthma phenotypes and to increase the power in association studies. Accordingly, the aim of this study was to evaluate the association between single nucleotide polymorphisms (SNPs) in candidate gene regions and continuous measures of asthma severity, in adult patients from the general population. In the Gene Environment Interactions in Respiratory Diseases (GEIRD) study (www.geird.org), 326 subjects (aged 20-64) with ever asthma were identified from the general population in Verona (Italy) between 2007 and 2010. A panel of 236 SNPs tagging 51 candidate gene regions (including one or more genes) was analysed. A symptom and treatment score (STS) and pre-bronchodilator FEV1% predicted were used as continuous measures of asthma severity. The association of each SNP with STS and FEV1% predicted was tested by fitting quasi-gamma and linear regression models, respectively, with gender, body mass index and smoking habits as potential confounders. The Simes multiple-test procedure was used for controlling the false discovery rate (FDR). SNP rs848 in the IL13 gene region (IL5/RAD50/IL13/IL4) was associated with STS (TG/GG vs TT genotype: uncorrected p-value = 0.00006, FDR-corrected p-value = 0.04), whereas rs20541 in the same gene region, in linkage disequilibrium with rs848 (r(2) = 0.94) in our sample, did not reach the statistical significance after adjusting for multiple testing (TC/CC vs TT: uncorrected p-value = 0.0003, FDR-corrected p-value = 0.09). Polymorphisms in other gene regions showed a non-significant moderate association with STS (IL12B, TNS1) or lung function (SERPINE2, GATA3, IL5, NPNT, FAM13A) only. After adjusting for multiple testing and potential confounders, SNP rs848 in the IL13 gene region is significantly associated with a continuous measure of symptom severity in adult subjects with ever asthma.
不同基因与哮喘严重程度的分类相关。然而，应使用连续性指标来捕捉哮喘表型的异质性，并提高关联研究的效能。因此，本研究旨在评估候选基因区域中的单核苷酸多态性（SNP）与普通人群成年患者哮喘严重程度的连续性指标之间的关联。在呼吸道疾病基因-环境相互作用（GEIRD）研究（www.geird.org）中，2007年至2010年间从意大利维罗纳的普通人群中确定了326名曾患哮喘的受试者（年龄在20 - 64岁）。分析了一组标记51个候选基因区域（包括一个或多个基因）的236个SNP。症状和治疗评分（STS）以及预计的支气管扩张剂前FEV1%被用作哮喘严重程度的连续性指标。分别通过拟合准伽马模型和线性回归模型，以性别、体重指数和吸烟习惯作为潜在混杂因素，来检验每个SNP与STS以及预计FEV1%之间的关联。使用西姆斯多重检验程序来控制错误发现率（FDR）。IL13基因区域（IL5/RAD50/IL13/IL4）中的SNP rs848与STS相关（TG/GG与TT基因型：未校正的p值 = 0.00006，FDR校正的p值 = 0.04），而同一基因区域中的rs20541，在我们的样本中与rs848处于连锁不平衡状态（r(2) = 0.94），在进行多重检验校正后未达到统计学显著性（TC/CC与TT：未校正的p值 = 0.0003，FDR校正的p值 = 0.09）。其他基因区域的多态性仅显示与STS（IL12B、TNS1）或肺功能（SERPINE2、GATA3、IL5、NPNT、FAM13A）存在非显著性的中度关联。在对多重检验和潜在混杂因素进行校正后，IL13基因区域中的SNP rs848与曾患哮喘的成年受试者症状严重程度的连续性指标显著相关。
