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• W2751826154 abstract "The severity of cystic fibrosis (CF) lung disease varies widely, even for Phe508del homozygotes. Heritability studies show that more than 50% of the variability reflects non-cystic fibrosis transmembrane conductance regulator (CFTR) genetic variation; however, the full extent of the pertinent genetic variation is not known.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.Nasal mucosal RNA from 134 patients with CF 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 the concordance of genomic and transcriptomic data. Association of gene expression with previously identified CF GWAS risk alleles was also tested.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 (human leukocyte antigen) genes. Ion transport and CFTR processing pathways, as well as HLA genes, were identified across differential gene expression and GWAS signals.Transcriptomic analyses of CF airway epithelia, coupled to genomic (GWAS) analyses, highlight 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." @default.
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• W2751826154 date "2018-01-01" @default.
• W2751826154 modified "2023-09-30" @default.
• W2751826154 title "Airway Mucosal Host Defense Is Key to Genomic Regulation of Cystic Fibrosis Lung Disease Severity" @default.
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• W2751826154 doi "https://doi.org/10.1164/rccm.201701-0134oc" @default.
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