Laurens J De Sadeleer1, Stijn E Verleden2, Jonas C Schupp3, John E McDonough4, Tinne Goos5, Jonas Yserbyt6, Elena Bargagli7, Paola Rottoli8, Naftali Kaminski4, Antje Prasse9, Wim A Wuyts5. 1. Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department CHROMETA, KU Leuven, Leuven, Belgium; Unit of Interstitial Lung Diseases, Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium. Electronic address: laurens.desadeleer@kuleuven.be. 2. Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department CHROMETA, KU Leuven, Leuven, Belgium; Antwerp Surgical Training, Anatomy and Research Centre, Antwerp University, Antwerp, Belgium. 3. Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT; Department of Pulmonology, Hannover Medical School, Hannover, Germany. 4. Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT. 5. Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department CHROMETA, KU Leuven, Leuven, Belgium; Unit of Interstitial Lung Diseases, Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium. 6. Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department CHROMETA, KU Leuven, Leuven, Belgium. 7. Respiratory Diseases and Lung Transplantation Unit, AOUS and Siena University, Siena, Italy. 8. Specialization School in Respiratory Diseases, Siena University, Siena, Italy. 9. Department of Pulmonology, Hannover Medical School, Hannover, Germany; Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany; German Centre for Lung Research, BREATH, Hannover, Germany; Department of Pneumology, University Medical Centre, Freiburg, Germany.
Abstract
BACKGROUND: Given the plethora of pathophysiologic mechanisms described in idiopathic pulmonary fibrosis (IPF), we hypothesize that the mechanisms driving fibrosis in IPF may be different from one patient to another. RESEARCH QUESTION: Do IPF endotypes exist and are they associated with outcome? STUDY DESIGN AND METHODS: Using a publicly available gene expression dataset retrieved from BAL samples of patients with IPF and control participants (GSE70867), we clustered IPF samples based on a dimension reduction algorithm specifically designed for -omics data, called DDR Tree. After clustering, gene set enrichment analysis was performed for functional annotation, associations with clinical variables and prognosis were investigated, and differences in transcriptional regulation were determined using motif enrichment analysis. The findings were validated in three independent publicly available gene expression datasets retrieved from IPF blood samples. RESULTS: One hundred seventy-six IPF samples from three centers were clustered in six IPF clusters, with distinct functional enrichment. Although clinical characteristics did not differ between the clusters, one cluster conferred worse sex-age-physiology score-corrected survival, whereas another showed a numeric trend toward worse survival (P = .08). The first was enriched for increased epithelial and innate and adaptive immunity signatures, whereas the other showed important telomere and mitochondrial dysfunction, loss of proteostasis, and increased myofibroblast signatures. The existence of these two endotypes, including the impact on survival of the immune endotype, was validated in three independent validation cohorts. Finally, we identified transcription factors regulating the expression of endotype-specific survival-associated genes. INTERPRETATION: Gene expression-based endotyping in IPF is feasible and can inform clinical evolution. As endotype-specific pathways and survival-associated transcription factors are identified, endotyping may open up the possibility of endotype-tailored therapy.
BACKGROUND: Given the plethora of pathophysiologic mechanisms described in idiopathic pulmonary fibrosis (IPF), we hypothesize that the mechanisms driving fibrosis in IPF may be different from one patient to another. RESEARCH QUESTION: Do IPF endotypes exist and are they associated with outcome? STUDY DESIGN AND METHODS: Using a publicly available gene expression dataset retrieved from BAL samples of patients with IPF and control participants (GSE70867), we clustered IPF samples based on a dimension reduction algorithm specifically designed for -omics data, called DDR Tree. After clustering, gene set enrichment analysis was performed for functional annotation, associations with clinical variables and prognosis were investigated, and differences in transcriptional regulation were determined using motif enrichment analysis. The findings were validated in three independent publicly available gene expression datasets retrieved from IPF blood samples. RESULTS: One hundred seventy-six IPF samples from three centers were clustered in six IPF clusters, with distinct functional enrichment. Although clinical characteristics did not differ between the clusters, one cluster conferred worse sex-age-physiology score-corrected survival, whereas another showed a numeric trend toward worse survival (P = .08). The first was enriched for increased epithelial and innate and adaptive immunity signatures, whereas the other showed important telomere and mitochondrial dysfunction, loss of proteostasis, and increased myofibroblast signatures. The existence of these two endotypes, including the impact on survival of the immune endotype, was validated in three independent validation cohorts. Finally, we identified transcription factors regulating the expression of endotype-specific survival-associated genes. INTERPRETATION: Gene expression-based endotyping in IPF is feasible and can inform clinical evolution. As endotype-specific pathways and survival-associated transcription factors are identified, endotyping may open up the possibility of endotype-tailored therapy.
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