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Children's Hospital of Pittsburgh
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Children's Hospital of Pittsburgh
The Celedón Lab for Pediatric Asthma Research

The Celedón Lab for Pediatric Asthma Research

Decoding the Enigmatic Causes of Asthma

The most common serious chronic disease in infants and children, asthma is caused by many factors, including genetics and environmental and behavioral factors such as diet, obesity, chronic stress, air pollution and more. Today, researchers are in the early stages of understanding these causes, and their precise relationship to pediatric asthma. Pulmonologist and genetic epidemiologist Juan C. Celedón, MD, DrPH, and his team have taken a leadership role in the identification of genetic factors and environmental exposures that influence the development of asthma and chronic obstructive pulmonary disease (COPD), particularly in ethnic minorities.

DNADr. Celedón’s team first identified MMP12 and TSLP as susceptibility genes for asthma- or COPD-phenotypes in humans, while also showing that racial ancestry partly explains marked differences in the burden of asthma and COPD between Puerto Ricans and Mexicans – the Hispanic paradox.

Moreover, Dr. Celedón’s group conducted the first epigenome-wide association study (EWAS) of atopy and atopic asthma in DNA from nasal (airway) epithelium from diverse youth in three cohorts, identifying DNA methylation changes that affect the expression of regulatory genes for epithelial integrity and immune responses, and accurately classify atopic asthma in youth. More recently, Dr. Celedón’s team showed that nasal epithelial transcriptomic profiles identify three asthma endotypes in youth, and that, contrary to prior assumptions, T2-low asthma endotypes are more common than T2-high asthma in school-aged children and young adults from predominantly minoritized groups. Such findings are paradigm-shifting and have major implications for identifying endotype-specific risk factors and developing biomarkers and novel therapeutic agents in asthma.

Dr. Celedón’s team first reported that child maltreatment is associated with asthma, and that a child maltreatment-asthma association in adults is substantially mediated by major depressive disorder and generalized anxiety disorder. Further, they have shown that violence-related distress and depression are associated with asthma and reduced bronchodilator responsiveness across life stages. Moreover, Dr. Celedón’s group first showed that post-traumatic stress disorder is associated with new-onset asthma in heavily traumatized adults. Such findings support a role for psychosocial stressors and stress-related disorders in the pathogenesis of asthma in children and adults. Based on this work and studies in omics (see above), Dr. Celedón’s team is now examining whether changes in DNA methylation and/or gene expression induced by violence or stress lead to persistent or new-onset asthma in young Puerto Rican adults, reduced response to treatment for asthma in minoritized children, and worse asthma outcomes in youth and adults.

Dr. Celedón’s team first demonstrated that overweight/obesity is associated with reduced response to inhaled corticosteroids in children with asthma, and then showed that overweight/obesity is associated with asthma in children with normal fractional exhaled nitric oxide (FeNO), but not in those with increased FeNO. More recently, they showed that obesity is associated with airway dysanapsis, and that this is linked to severe asthma exacerbations in obese children. These results support those of experimental models showing that obesity can lead to asthma through non-allergic mechanisms.

After conducting several observational studies, Dr. Celedón’s group led the first randomized placebo-controlled trial of vitamin D supplementation to prevent severe asthma exacerbations in children with low vitamin D levels, which showed no benefit in children with vitamin D levels of 14-29 ng/ml (comprising most children with vitamin D levels <30 ng/ml in the U.S.). This has helped to markedly reduce routine testing of vitamin D levels in children with asthma.