Plasma Metabolomic Signatures of Chronic Obstructive Pulmonary Disease and the Impact of Genetic Variants on Phenotype-Driven Modules

• DOI: 10.1089/nsm.2020.0009
• Publication Date: 2021-01-04T22:09:21Z
• Authors: Lucas A. Gillenwater; Katherine A. Pratte; Brian D. Hobbs; Michael H. Cho; Yonghua Zhuang; Eitan Halper-Stro...; Charmion Cruicksh...; Nichole Reisdorph; Irina Petrache; Wassim W. Labaki; Wanda K. O'Neal; Victor E. Ortega; Dean P. Jones; Karan Uppal; Sean Jacobson; Gregory Michelotti; Christine H. Wendt; Katerina J. Kechris; Russell P. Bowler
• Keywords: Metabolome; Chronic bronchitis

Background: Small studies have recently suggested that there are specific plasma metabolic signatures in chronic obstructive pulmonary disease (COPD), but been no large comprehensive study of metabolomic COPD also integrate genetic variants. Materials and Methods: Fresh frozen from 957 non-Hispanic white subjects COPDGene was used to quantify 995 metabolites with Metabolon's global metabolomics platform. Metabolite associations five phenotypes (chronic bronchitis, exacerbation frequency, percent emphysema, post-bronchodilator forced expiratory volume at one second [FEV1]/forced vital capacity [FVC], FEV1 predicted) were assessed. A metabolome-wide association performed find metabolite levels. Significantly associated single-nucleotide polymorphisms tested for replication independent platforms cohorts. phenotype-driven modules identified network analysis integrated assess gene-metabolite-phenotype interactions. Results: Of tested, 147 (14.8%) significantly least 1 phenotype. Associations airflow obstruction enriched diacylglycerols branched chain amino acids. Genetic observed 109 (11%) metabolites, 72 (66%) which replicated an cohort. For 20 more than 20% variance explained by genetics. sparse identified, often containing missed previous testing. the 26 modules, 6 contained significant met-QTLs, although little module Conclusion: dysregulation systemic metabolism predominantly found characterized obstruction, where we robust heritable effects on individual abundances. However, analysis, increased statistical power detect previously classic regression analyses, revealed influence modest when compared clinical environmental factors.