Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Tsukuba Medical Center, Tsukuba, Japan.
PLoS One. 2024 Mar 8;19(3):e0300000. doi: 10.1371/journal.pone.0300000. eCollection 2024.
Disturbance of mucociliary clearance is an important factor in the pathogenesis of asthma. We hypothesized that common variants in genes responsible for ciliary function may contribute to the development of asthma with certain phenotypes.
Three independent adult Japanese populations (including a total of 1,158 patients with asthma and 2,203 non-asthmatic healthy participants) were studied. First, based on the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/), we selected 12 common single-nucleotide polymorphisms (SNPs) with molecular consequences (missense, nonsense, and 3'-untranslated region mutation) in 5 primary ciliary dyskinesia (PCD)-related genes and calculated a PCD-genetic risk score (GRS) as a cumulative effect of these PCD-related genes. Second, we performed a two-step cluster analysis using 3 variables, including PCD-GRS, forced expiratory volume in 1 second (%predicted FEV1), and age of asthma onset.
Compared to adult asthma clusters with an average PCD-GRS, clusters with high and low PCD-GRS had similar overall characteristics: adult-onset, female predominance, preserved lung function, and fewer features of type 2 immunity as determined by IgE reactivity and blood eosinophil counts. The allele frequency of rs1530496, a SNP representing an expression quantitative trait locus (eQTL) of DNAH5 in the lung, showed the largest statistically significant difference between the PCD-GRS-High and PCD-GRS-Low asthma clusters (p = 1.4 x 10-15).
Genes associated with PCD, particularly the common SNPs associated with abnormal expression of DNAH5, may have a certain influence on the development of adult-onset asthma, perhaps through impaired mucociliary clearance.
黏液纤毛清除功能障碍是哮喘发病机制中的一个重要因素。我们假设，负责纤毛功能的基因中的常见变异可能导致具有某些表型的哮喘发生。
研究了三个独立的成年日本人群（共包括 1158 例哮喘患者和 2203 例非哮喘健康对照者）。首先，根据 ClinVar 数据库（https://www.ncbi.nlm.nih.gov/clinvar/），我们选择了 5 个原发性纤毛运动障碍（PCD）相关基因中具有分子后果（错义、无义和 3'-非翻译区突变）的 12 个常见单核苷酸多态性（SNP），并计算了这些 PCD 相关基因的累积效应作为 PCD 遗传风险评分（GRS）。其次，我们使用 3 个变量（PCD-GRS、第 1 秒用力呼气量占预计值的百分比（%predicted FEV1）和哮喘发病年龄）进行了两步聚类分析。
与平均 PCD-GRS 的成人哮喘聚类相比，高 PCD-GRS 和低 PCD-GRS 聚类具有相似的总体特征：成人发病、女性为主、肺功能保留以及 IgE 反应性和血嗜酸性粒细胞计数等 2 型免疫特征较少。rs1530496 的等位基因频率，该 SNP 代表 DNAH5 在肺部的表达数量性状基因座（eQTL），在 PCD-GRS-高和 PCD-GRS-低哮喘聚类之间显示出最大的统计学显著差异（p=1.4×10-15）。
与 PCD 相关的基因，特别是与 DNAH5 异常表达相关的常见 SNP，可能对成人发病的哮喘有一定影响，可能是通过黏液纤毛清除功能受损所致。
