Gene co-expression networks in whole blood implicate multiple interrelated molecular pathways in obese asthma

Abstract

Asthmatic children who develop obesity have poorer outcomes compared to those that do not, including poorer control, more severe symptoms, and greater resistance to standard treatment. The aim of this study was to characterize the biology of childhood asthma complicated by adult obesity. Gene expression networks are powerful statistical tools for characterizing the underpinnings of human disease that leverage the putative co-regulatory relationships of genes to infer biological pathways altered in disease states. We performed weighted gene co-expression network analysis (WGCNA) of adult gene expression data in whole blood from 514 subjects from the Childhood Asthma Management Program (CAMP). We identified a multivariate model in which four gene coexpression network modules were associated with incident obesity in CAMP (each P < 0.05). The module memberships were enriched for genes in pathways related to platelets, integrins, extracellular matrix, smooth muscle, NF-κB signaling, and Hedgehog signaling. We then performed module preservation and association replication analyses in 418 subjects from two independent asthma cohorts (one pediatric and one adult). The network structures of each of the four obese asthma modules were significantly preserved in both replication cohorts (permutation P = 9.999E-05). The corresponding module gene sets were significantly enriched for differential expression in obese subjects in both replication cohorts (each P < 0.05). Our gene co-expression network profiles thus implicate multiple inflammatory pathways in the biology of an important endotype of obese asthma.