Rationale: The severity of cystic fibrosis (CF) lung disease varies widely, even for Phe508del homozygotes. Heritability studies show that >50% of the variability reflects non-CFTR genetic variation; however the full extent of the pertinent genetic variation is not known. Objectives: We sought to identify novel CF disease-modifying mechanisms using an integrated approach based on analyzing “in vivo” CF airway epithelial gene expression, complemented with genome-wide association study (GWAS) data. Methods: Nasal mucosal RNA from 134 CF patients was used for RNA sequencing. We tested for associations of transcriptomic (gene expression) data with a quantitative phenotype of CF lung disease severity. Pathway analysis of CF GWAS data (n = 5,659 patients) was performed to identify novel pathways and assess concordance of genomic and transcriptomic data. Association of gene expression with previously identified CF GWAS risk alleles was also tested. Measurements and Main Results: Significant evidence of heritable gene expression was identified. Gene expression pathways relevant to airway mucosal host defense were significantly associated with CF lung disease severity, including viral infection, inflammation/inflammatory signaling, lipid metabolism, apoptosis, ion transport, Phe508del CFTR processing, and innate immune responses, including HLA genes. Ion transport and CFTR processing pathways, and HLA genes, were identified across differential gene expression and GWAS signals. Conclusion: Transcriptomic analyses in CF airway epithelia, coupled to genomic (GWAS) analyses, highlights the role of heritable host defense variation in determining the pathophysiology of CF lung disease. The identification of these pathways provides opportunities to pursue targeted interventions to improve CF lung health.

中文翻译：

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气道粘膜宿主防御是囊性纤维化肺病严重程度基因组调控的关键

理由：即使对于Phe508del纯合子，囊性纤维化（CF）肺部疾病的严重程度也有很大差异。遗传性研究表明，> 50％的变异性反映了非CFTR遗传变异；然而，有关遗传变异的全部范围尚不清楚。目的：我们试图通过基于“体内” CF气道上皮基因表达分析并辅以全基因组关联研究（GWAS）数据的综合方法，来确定新型的CF疾病缓解机制。方法：将134例CF患者的鼻黏膜RNA用于RNA测序。我们测试了转录组（基因表达）数据与CF肺病严重程度定量表型的关联。CF GWAS数据的路径分析（n = 5 进行了659例患者的研究，以鉴定新的途径并评估基因组和转录组数据的一致性。还测试了基因表达与先前确定的CF GWAS风险等位基因的关联。测量和主要结果：确定了可遗传基因表达的重要证据。与气道粘膜宿主防御相关的基因表达途径与CF肺部疾病的严重程度显着相关，包括病毒感染，炎症/炎症信号传导，脂质代谢，细胞凋亡，离子转运，Phe508del CFTR加工以及包括HLA基因在内的先天免疫应答。跨差异基因表达和GWAS信号确定了离子转运和CFTR处理途径以及HLA基因。结论：CF气道上皮细胞的转录组学分析，加上基因组（GWAS）分析，强调了可遗传的宿主防御变异在确定CF肺病的病理生理学中的作用。这些途径的鉴定为寻求有针对性的干预措施以改善CF肺健康提供了机会。