Friday, May 9, 2025
5/9/2025
Relevance of RPS27L expression quantitative trait locus in pediatric obesity-related asthma - Obesity-related asthma is the most consistently reported pediatric non-atopic asthma phenotype that is associated with high disease burden and is poorly responsive to asthma medications. It is a major subset of pediatric asthma that is increasing in incidence since 20% of children in the U.S. are overweight/obese, with higher rates observed in Hispanic and African American children. However, not all children who gain weight develop obesity-related asthma, suggesting that genetic susceptibility plays a role. Thus, identification of genetic risk markers for obesity-related asthma will offer opportunities for primary prevention. Investigation of biologic mechanisms underlying the genetic risk will identify novel therapeutic targets for obesity-related asthma, which has no effective treatment options. Our research program is leading the investigation of immunobiology of obesity-related asthma in minority children. In peripheral blood from Hispanic and African American children, we found non-atopic immune responses with T helper (TH)1 cell polarization that correlated with pulmonary function deficits in obesity-related asthma, and was associated with upregulation of Cell Division Cycle 42 (CDC42) pathway in TH cells, which plays an integral role in TH cell migration and differentiation, particularly to TH1 cells; inhibition of CDC42 led to inhibition of TH1 but not TH2 cytokines. Investigation of the contribution of genetic variants to immunobiology of obesity-related asthma in minority children identified a single nucleotide polymorphism (SNP) at rs6494395 locus that functions as an expression quantitative trait locus (eQTL) in TH cells for the gene encoding for ribosomal protein S27 like (RPS27L) protein. The minor allele (C allele), that is 2 to 4 times more prevalent in Hispanic and African populations, was associated with RPS27L downregulation. All three children with C/C genotype were obese with asthma. RPS27L downregulation and homozygosity for C allele were independent predictors of 14% and 10% (respectively) lower FEV1/FVC ratio in obese children with asthma. We therefore speculate that the C allele at the rs6494395 locus is relevant to pediatric obesity-related asthma. Although there is no known links between RPS27L, TH1 cells, CDC42, or asthma, RPS27L is a target and a modulator of p53, which plays a key role in control of TH cell proliferation and modulates CDC42 to control cell migration. These findings form the premise for this proposal. We hypothesize that C allele at rs6494395 locus is a novel at-risk allele that confers susceptibility to non-atopic obesity-related asthma in minority children by downregulating RPS27L which downregulates p53 activity in TH cells, causing increased TH1 cell proliferation and CDC42-mediated cell migration. To test our hypothesis, we will investigate 1) the ancestry of C allele at rs6494395, and its links with RPS27L expression, TH1 polarization, and disease burden in obese children with asthma, relative to obese children without asthma, and healthy-weight children with and without asthma, and 2) novel mechanistic links between RPS27L, p53, and CDC42 in healthy TH1 cells and the presence of these links in TH1 cells from obese children with asthma.
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