The Association of Metabolic Measures with Gene Expression in T Helper Cells from Obese Children with Asthma
Open AccessObjective: As incident obesity increases in the population, the prevalence of asthma among obese children is on the rise. This phenomenon is more pronounced among African American and Hispanic children. Children with obesity-related asthma have higher disease severity and usually respond poorly to treatment. Obesity-related metabolic abnormalities have been found to play a role in the pathophysiology of obesity-related asthma, including by influencing differential gene expression in Th or CD4+ T cells in obese children with asthma. Differential gene expression in obese asthmatic Th cells is associated with markers of disease burden including lung function. However, the mechanism by which these metabolic complications lead to disease-related immune responses in obesity-related asthma is unclear. In this study, we analyzed the contribution of metabolic measures to the differential expression of CD4+ T cell genes in obese and normal-weight asthmatic children to quantify the contribution of metabolic measures to the differential expression of disease-related genes.Methods: We analyzed clinical and RNA-seq data from African American and Hispanic children with normal-weight asthma and obesity-related asthma. After preprocessing the data, the DESeq2 package and other relevant libraries, statistic method was used in the R programming environment to analyze clinical data and screen differentially expressed genes between normal-weight asthma and obesity-related asthma. Correlation analysis between differentially expressed genes and metabolic measures was performed on the two groups, respectively. DAVID online tool was used for GO annotation and KEGG pathway enrichment analysis of the differentially expressed genes in both study groups. Also, STRING online database and Cytoscape software were utilized for protein-protein interaction network analysis. Results: Our study sample of 101 children included 54 normal-weight children with asthma, and 47 obese children with asthma. Obese children with asthma had significantly higher BMI, insulin, and leptin levels than normal-weight asthmatic children, while the adiponectin level was significantly lower than that of normal-weight asthmatic children. Screening of differentially expressed genes in the two groups of children with asthma identified, 784 differentially expressed genes in obese asthmatic Th cells, of which 759 were up-regulated and 25 were down-regulated. In the obese asthma group, we identified 66 genes of the 150 gens are related to insulin were filtered into the protein-protein interaction (PPI) network. Among them, we found that DCN, DAA2IP, NLGN1 and KDR and other genes appeared frequently in the biological processes and their expression was significantly up-regulated in the obese group with asthma. Among the biological processes enriched for association with insulin include innate immune response, inflammation, and regulation of respiratory gaseous exchange by neurological system process. Similarly, we found that 103 genes co-related with leptin, 28 were filtered into the protein-protein interaction (PPI) network and the biological process of differentially expressed genes, we found that CCR2 and TRAF6 appeared more frequently in the obese group, which mainly involved in processes such as innate and acquired immunity and inflammation. KEGG analysis of genes associated with metabolic indicators in normal-weight asthmatic children and obese children with asthma respectively showed that genes associated with metabolic indicators in the obese children with asthma are more significant in metabolic-related signaling pathways, Nicotinate and nicotinamide metabolism, which correlated with leptin. The signaling pathways related to metabolism that correlated with insulin and adiponectin were enriched for tryptophan metabolism. Conclusion: This study showed evidence of differentially expressed genes between obese asthma and normal-weight asthma. BMI, insulin, and leptin levels of obese children with asthma were significantly higher, while the adiponectin levels were significantly lower. These metabolic measures were differentially associated with several immune and metabolic pathways in obese asthmatic Th1 cells.
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