Club cell secretory protein and lung function in children with cystic fibrosis |
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| Affiliation: | 1. Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, United States;2. Department of Biostatistics, University of Washington, Seattle, WA, United States;3. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, United States;4. Brotman-Baty Institute for Precision Medicine, Seattle, WA, United States;5. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, United States;6. Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States;7. Department of Pediatrics, Children''s Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, CO, United States;8. Department of Genome Sciences, University of Washington, Seattle, WA, United States;9. Department of Pediatrics, University of Arizona, Tucson, AZ, United States;10. Department of Medicine, University of Arizona, Tucson, AZ, United States;1. Leeds Institute of Medical Research at St James''s, University of Leeds, Leeds, United Kingdom;2. Leeds Adult Cystic Fibrosis Unit, St James''s University Hospital, Leeds, United Kingdom;1. McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States;2. Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD 21287, United States;3. Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States;4. Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada;5. Cystic Fibrosis Foundation, Bethesda, MD 20814, United States;6. Department of Respirology, Adult Cystic Fibrosis Program, St. Michael''s Hospital, Toronto, Ontario, Canada;7. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada;8. IRCCS Istituto Giannina Gaslini, Cystic Fibrosis Center, Genoa, Italy;1. Department of Physiotherapy and Occupational Therapy, Aarhus University Hospital, Aarhus, Denmark;2. Cystic Fibrosis Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark;3. Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark;1. Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States;2. Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States;3. State Hygienic Laboratory at the University of Iowa, Coralville, IA, United States;1. Department of Pathophysiology and Transplantation, University of Milan, Italy;2. Internal Medicine Department, Respiratory Unit and Cystic Fibrosis Adult Center. Fondazione IRCCS Ca'' Granda Ospedale Maggiore Policlinico, Milan, Italy;3. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy;4. Cardiology Unit, Internal Medicine Department, Fondazione IRCCS Ca'' Granda Ospedale Maggiore Policlinico, Milan, Italy;5. IRCCS Humanitas Research Hospital, Respiratory Unit, Rozzano, Italy;1. CHU Nantes, Service de Pneumologie, Institut du Thorax, Nantes, France;2. Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France;3. Université Paris Cité, Inserm U1016, Institut Cochin, Paris, France;4. Pulmonary Department and National Cystic Fibrosis Reference Centre, Cochin Hospital; Assistance Publique Hôpitaux de Paris, Paris, France |
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| Abstract: | BackgroundClub cell secretory protein (CC16) exerts anti-inflammatory functions in lung disease. We sought to determine the relation of serum CC16 deficits and genetic variants that control serum CC16 to lung function among children with cystic fibrosis (CF).MethodsWe used longitudinal data from CF children (EPIC Study) with no positive cultures for Pseudomonas aeruginosa prior to enrollment. Circulating levels of CC16 and an inflammatory score (generated from CRP, SAA, calprotectin, G-CSF) were compared between participants with the lowest and highest FEV1 levels in adolescence (LLF and HLF groups, respectively; N = 130-per-group). Single nucleotide variants (SNVs) in the SCGB1A1, EHF-APIP loci were tested for association with circulating CC16 and with decline of FEV1 and FEV1/FVC% predicted levels between ages 7–16 using mixed models.ResultsCompared with the HLF group, the LLF group had lower levels of CC16 (geometric means: 8.2 vs 6.5 ng/ml, respectively; p = 0.0002) and higher levels of the normalized inflammatory score (-0.21 vs 0.21, p = 0.0007). Participants in the lowest CC16 and highest inflammation tertile had the highest odds for having LLF (p<0.0001 for comparison with participants in the highest CC16 and lowest inflammation tertile). Among seven SNVs associated with circulating CC16, the top SNV rs3741240 was associated with decline of FEV1/FVC and, marginally, FEV1 (p = 0.003 and 0.025, respectively; N = 611 participants, 20,801 lung function observations).ConclusionsSerum CC16 deficits are strongly associated with severity of CF lung disease and their effects are additive with systemic inflammation. The rs3741240 A allele is associated with low circulating CC16 and, possibly, accelerated lung function decline in CF. |
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| Keywords: | Cystic fibrosis Lung function |
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