Functional Genomics of the Pediatric Obese Asthma Phenotype Reveal Enrichment of Rho-GTPase Pathways.

RATIONALE: Obesity-related asthma disproportionately affects minority children, and is associated with non-atopic T helper (Th) 1 polarized inflammation that correlates with pulmonary function deficits. Its underlying mechanisms are poorly understood. OBJECTIVES: Utilize functional genomics to identify cellular mechanisms associated with non-atopic inflammation in obese asthmatic minority children. METHODS: CD4+Th cells from 59 obese asthmatic and 61 normal-weight asthmatic Hispanic and African American children underwent quantification of the transcriptome and DNA methylome, and genotyping. Expression and methylation quantitative trait loci (eQTLs and meQTLs) revealed the contribution of genetic variation to transcription and DNA methylation. Adjusting for Th cell subtype proportions discriminated loci where transcription or methylation differences were driven by differences in subtype proportions from loci that were independently associated with obesity-related asthma. MEASUREMENTS AND MAIN RESULTS: Obese asthmatics had more memory and fewer naive Th cells than normal-weight asthmatics. Differentially expressed and methylated genes, and meQTLs in obese asthmatics, independent of Th cell subtype proportions, were enriched in Rho-GTPase pathways. Inhibition of CDC42, one of the Rho-GTPases associated with Th cell differentiation, was associated with downregulation of IFNgamma, but not IL-4 gene. Differential expression of RPS27L gene, part of the p53-mTOR pathway, was due to non-random distribution of eQTL variants between groups. Differentially expressed and/or methylated genes, including RPS27L, were associated with pulmonary function deficits in obese asthmatics. CONCLUSIONS: We found enrichment of Rho-GTPase pathways in obese asthmatic Th cells, identifying them as a novel therapeutic target for obesity-related asthma, a disease that is sub-optimally responsive to current therapies.