Accordini Simone, Lando Valentina, Calciano Lucia, Bombieri Cristina, Malerba Giovanni, Margagliotti Antonino, Minelli Cosetta, Potts James, van der Plaat Diana A, Olivieri Mario
Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, Verona 37134, Italy.
Biology and Genetics Section, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona 37134, Italy.
J Breath Res. 2023 Oct 6;18(1). doi: 10.1088/1752-7163/acfbf1.
Nitric oxide has different roles in asthma as both an endogenous modulator of airway function and a pro-inflammatory mediator. Fractional exhaled nitric oxide (FeNO) is a reliable, quantitative, non-invasive, simple, and safe biomarker for assessing airways inflammation in asthma. Previous genome-wide and genetic association studies have shown that different genes and single nucleotide polymorphisms (SNPs) are linked to FeNO. We aimed at identifying SNPs in candidate genes or gene regions that are associated with FeNO in asthma. We evaluated 264 asthma cases (median age 42.8 years, female 47.7%) who had been identified in the general adult population within the Gene Environment Interactions in Respiratory Diseases survey in Verona (Italy; 2008-2010). Two hundred and twenty-one tag-SNPs, which are representative of 50 candidate genes, were genotyped by a custom GoldenGate Genotyping Assay. A two-step association analysis was performed without assuming angenetic model: step (1) a machine learning technique [gradient boosting machine (GBM)] was used to select the 15 SNPs with the highest variable importance measure; step (2) the GBM-selected SNPs were jointly tested in a linear regression model with natural log-transformed FeNO as the normally distributed outcome and with age, sex, and the SNPs as covariates. We replicated our results within an independent sample of 296 patients from the European Community Respiratory Health Survey III. We found that SNP rs987314 in family with sequence similarity 13 member A () and SNP rs3218258 in interleukin 2 receptor subunit beta () gene regions are significantly associated with FeNO in adult subjects with asthma. These genes are involved in different mechanisms that affect smooth muscle constriction and endothelial barrier function responses (), or in immune response processes (). Our findings contribute to the current knowledge on FeNO in asthma by identifying two novel SNPs associated with this biomarker of airways inflammation.
一氧化氮在哮喘中具有不同作用，既是气道功能的内源性调节剂，又是促炎介质。呼出一氧化氮分数（FeNO）是评估哮喘气道炎症的一种可靠、定量、无创、简单且安全的生物标志物。先前的全基因组和基因关联研究表明，不同基因和单核苷酸多态性（SNP）与FeNO相关。我们旨在识别哮喘中与FeNO相关的候选基因或基因区域中的SNP。我们评估了在意大利维罗纳进行的呼吸道疾病基因环境相互作用调查（2008 - 2010年）中从普通成年人群中识别出的264例哮喘病例（中位年龄42.8岁，女性占47.7%）。通过定制的金标准基因分型检测对代表50个候选基因的221个标签SNP进行基因分型。在不假设遗传模型的情况下进行两步关联分析：步骤（1）使用机器学习技术[梯度提升机（GBM）]选择可变重要性测量最高的15个SNP；步骤（2）在以自然对数转换的FeNO为正态分布结果且以年龄、性别和SNP为协变量的线性回归模型中对GBM选择的SNP进行联合测试。我们在来自欧洲共同体呼吸健康调查III的296名患者的独立样本中重复了我们的结果。我们发现，序列相似性家族13成员A（ ）中的SNP rs987314和白细胞介素2受体亚基β（ ）基因区域中的SNP rs3218258与成年哮喘患者的FeNO显著相关。这些基因参与影响平滑肌收缩和内皮屏障功能反应（ ）的不同机制，或参与免疫反应过程（ ）。我们的发现通过识别与这种气道炎症生物标志物相关的两个新SNP，为当前关于哮喘中FeNO的知识做出了贡献。
