Gene expression signatures of shortened-telomere-associated fibrotic interstitial lung disease

Shortened telomeres contribute to the pathogenesis of a subset of pulmonary fibrosis through mechanisms that remain unclear. We compared the expression of fibrosis-related genes in explanted lungs of pulmonary fibrosis patients with versus without shortened telomeres, to identify possible molecular mechanisms of pulmonary fibrosis pathogenesis in these patients. Telomere length was assessed using flow cytometry fluorescence in-situ hybridization on peripheral blood. Lymphocyte telomere length <10th percentile was considered shortened. Gene expression was assessed using the NanoString Human Fibrosis v2 Panel (782 genes) on whole slide sections of explanted lungs with pulmonary fibrosis. Gene expression data was obtained for 39 patients (17 with and 22 without shortened telomeres). Gene set enrichment analysis identified significant differential regulation of cholesterol metabolism and the 'regulation of tumor necrosis factor-mediated signaling pathway' gene ontology term in the shortened telomere group. Thirty-six genes were significantly differentially expressed in the shortened telomere samples, including increased expression of tumor necrosis factor pathway (NCF4, NR1H4) and cholesterol metabolism (APOA1, APOH, LIPC) genes in the shortened telomere group. Differential expression of these 36 genes was most pronounced in 5 of the 17 shortened telomere cases. This study highlights molecular heterogeneity within explanted lung tissue of patients with shortened telomeres and pulmonary fibrosis, with signatures of altered cholesterol metabolism and tumor necrosis factor signaling in a subset of shortened telomere cases. We highlight NCF4, NR1H4, APOA1, APOH and LIPC as differentially expressed genes in a subgroup of shortened telomere pulmonary fibrosis patients.