Somatic mutations in chronic lung disease are associated with reduced lung function
Somatic mutations in chronic lung disease are associated with reduced lung function
Abstract Among human organs, the lung harbors one of the highest rates of somatic mutations. However, the relationship of these mutations to lung disease and function is not known. We analyzed the somatic mutational pattern from 1,251 samples of normal and diseased non-cancerous lung tissue from the Lung Tissue Research Consortium using RNA-seq. In two of the most common diseases represented in our dataset, chronic obstructive pulmonary disease (COPD, 29%) and idiopathic pulmonary fibrosis (IPF, 13%), we found a significantly increased burden of somatic mutations compared to normal. Using deconvoluted cell type proportions, we found that a major predictor of somatic mutations was the airway to alveolar cell proportion and pathogenic cell types. We also found that mutational burden was associated with reduced lung function. This relationship remained even after adjustment for age, sex, smoking, and cell type proportion and in COPD and IPF. Our identification of an increased prevalence of somatic mutation in diseased lung that correlates with cell type proportion and disease severity highlights for the first time the role of somatic mutational processes in lung disease genetics.
Castaldi Peter J.、Cool Carlyne D.、Hersh Craig P.、Khan M.A. Wasay、Miller Peter G.、Limper Andrew H.、Criner Gerard J.、Brown Kevin、Martinez Fernando、Demeo Dawn、Cho Michael H.、Bick Alexander G.、Sciurba Frank、Barwick Lucas、Flaherty Kevin、Hobbs Brian D.、Silverman Edwin K.、Wise Robert、Yun Jeong H.、Ghosh Auyon
Channing Division of Network Medicine, Department of Medicine, Brigham and Women?ˉs Hospital||Harvard Medical SchoolDivision of Pathology, Department of Medicine, National Jewish HealthChanning Division of Network Medicine, Department of Medicine, Brigham and Women?ˉs Hospital||Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women?ˉs Hospital||Harvard Medical SchoolDivision of Genetic Medicine, Department of Medicine, Vanderbilt UniversityHarvard Medical School||Center for Cancer Research, Massachusetts General HospitalDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mayo ClinicThoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple UniversityDepartment of Medicine, National Jewish HealthDepartment of Medicine, Weill Cornell Medical CollegeChanning Division of Network Medicine, Department of Medicine, Brigham and Women?ˉs Hospital||Harvard Medical SchoolChanning Division of Network Medicine, Department of Medicine, Brigham and Women?ˉs Hospital||Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women?ˉs Hospital||Harvard Medical SchoolDivision of Genetic Medicine, Department of Medicine, Vanderbilt UniversityDivision of Pulmonary, Allergy and Critical Care Medicine, University of PittsburghEmmesDivision of Pulmonary & Critical Care Medicine, University of Michigan Health SystemChanning Division of Network Medicine, Department of Medicine, Brigham and Women?ˉs Hospital||Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women?ˉs Hospital||Harvard Medical SchoolChanning Division of Network Medicine, Department of Medicine, Brigham and Women?ˉs Hospital||Harvard Medical SchoolDepartment of Medicine, Johns Hopkins MedicineChanning Division of Network Medicine, Department of Medicine, Brigham and Women?ˉs Hospital||Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women?ˉs Hospital||Harvard Medical SchoolPulmonary Critical Care and Sleep Medicine, Upstate Medical University
基础医学遗传学生理学
Castaldi Peter J.,Cool Carlyne D.,Hersh Craig P.,Khan M.A. Wasay,Miller Peter G.,Limper Andrew H.,Criner Gerard J.,Brown Kevin,Martinez Fernando,Demeo Dawn,Cho Michael H.,Bick Alexander G.,Sciurba Frank,Barwick Lucas,Flaherty Kevin,Hobbs Brian D.,Silverman Edwin K.,Wise Robert,Yun Jeong H.,Ghosh Auyon.Somatic mutations in chronic lung disease are associated with reduced lung function[EB/OL].(2025-03-28)[2025-04-28].https://www.medrxiv.org/content/10.1101/2023.03.03.23286771.点此复制
评论