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

Background 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. 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. Objective The aim of this study was to characterize the biology of childhood asthma complicated by adult obesity. Methods We performed weighted gene co-expression network analysis (WGCNA) of gene expression data in whole blood from 514 adult subjects from the Childhood Asthma Management Program (CAMP). We then performed module preservation and association replication analyses in 418 subjects from two independent asthma cohorts (one pediatric and one adult). Results We identified a multivariate model in which four gene co-expression 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. 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). Conclusions Our gene co-expression network profiles thus implicate multiple interrelated pathways in the biology of an important endotype of obese asthma. Key Messages We hypothesized that individuals with asthma complicated by obesity had distinct blood gene expression signatures. Gene co-expression network analysis implicated several inflammatory biological pathways in one form of obese asthma. Capsule Summary This work addresses a knowledge gap about the molecular relationship between asthma and obesity, suggesting that an endotype of obese asthma, known as asthma complicated by obesity, is underpinned by coherent biological mechanisms. Abbreviations CAMP Childhood Asthma Management Program WGCNA weighted gene co-expression network analysis Asthma BRIDGE Asthma BioRepository for Integrative Genomic Exploration GACRS Genetics of Asthma in Costa Rica Study CHS Southern California Children’s Health Study BMI body mass index BIC Bayes Information Criterion HUGO Human Genome Organisation PC principal component GSEA gene set enrichment analysis IL-1 interleukin-1 Hh signaling Hedgehog signaling