CDC42-related genes are upregulated in helper T cells from obese asthmatic children

Background Pediatric obesity-related asthma is more severe and less responsive to medications than asthma in normal-weight children. Obese asthmatic children have nonatopic T H 1-polarized systemic inflammation that correlates with pulmonary function deficits, but the pathways underlying T H 1-polarized inflammation are not well understood. Objective We compared the CD4 + T-cell transcriptome in obese children with asthma with that in normal-weight children with asthma to identify key differentially expressed genes associated with T H 1-polarized inflammation. Methods CD4 + T-cell transcriptome–wide differential gene expression was compared between 21 obese and 21 normal-weight children by using directional RNA sequencing. High-confidence differentially expressed genes were verified in the first cohort and validated in a second cohort of 20 children (10 obese and 10 normal-weight children) by using quantitative RT-PCR. Results Transcriptome-wide differential gene expression among obese asthmatic children was enriched for genes, including VAV2 , DOCK5 , PAK3 , PLD1 , CDC42EP4 , and CDC42PBB , which are associated with CDC42, a small guanosine triphosphate protein linked to T-cell activation. Upregulation of MLK3 and PLD1 , genes downstream of CDC42 in the mitogen-activated protein kinase and mammalian target of rapamycin pathways and the inverse correlation of CDC42EP4 and DOCK5 transcript counts with FEV 1 /FVC ratio together support a role of CDC42 in the T H 1 polarization and pulmonary function deficits found in patients with obesity-related asthma. Conclusions Our study identifies the CDC42 pathway as a novel target that is upregulated in T H cells of obese asthmatic children, suggesting its role in nonatopic T H 1-polarized systemic inflammation and pulmonary function deficits found in patients with pediatric obesity-related asthma.