A Genetic Risk Score Associated with Chronic Obstructive Pulmonary Disease Susceptibility and Lung Structure on Computed Tomography

作者：Elizabeth C. Oelsner, Victor E. Ortega, Benjamin M. Smith, Jennifer N. Nguyen, Ani W Manichaikul, Eric A. Hoffman, Xiuqing Guo, Kent D. Taylor, Prescott G. Woodruff, David J. Couper, Nadia N. Hansel, Fernando J. Martínez, Robert Paine, MeiLan King Han, Christopher B. Cooper, Mark T. Dransfield, Gerard J. Criner, Jerry A. Krishnan, Russell Paul Bowler, Eugene R. Bleecker, Stephen P. Peters, Stephen S. Rich, Deborah A. Meyers, Jerome I. Rotter, R. Graham Barr · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2019 · DOI：10.1164/rccm.201812-2355oc · 被引用次数：50 · 研究领域：Chronic Obstructive Pulmonary Disease (COPD) Research、Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Asthma and respiratory diseases

Abstract Rationale Chronic obstructive pulmonary disease (COPD) has been associated with numerous genetic variants, yet the extent to which its genetic risk is mediated by variation in lung structure remains unknown. Objectives To characterize associations between a genetic risk score (GRS) associated with COPD susceptibility and lung structure on computed tomography (CT). Methods We analyzed data from MESA Lung (Multi-Ethnic Study of Atherosclerosis Lung Study), a U.S. general population–based cohort, and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). A weighted GRS was calculated from 83 SNPs that were previously associated with lung function. Lung density, spatially matched airway dimensions, and airway counts were assessed on full-lung CT. Generalized linear models were adjusted for age, age squared, sex, height, principal components of genetic ancestry, smoking status, pack-years, CT model, milliamperes, and total lung volume. Measurements and Main Results MESA Lung and SPIROMICS contributed 2,517 and 2,339 participants, respectively. Higher GRS was associated with lower lung function and increased COPD risk, as well as lower lung density, smaller airway lumens, and fewer small airways, without effect modification by smoking. Adjustment for CT lung structure, particularly small airway measures, attenuated associations between the GRS and FEV1/FVC by 100% and 60% in MESA and SPIROMICS, respectively. Lung structure (P < 0.0001), but not the GRS...