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 FEV1/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.