Chronic stress, omics, and asthma

Abstract

The U.S. has the highest rate of firearm‐related deaths of all economically developed nations. Current evidence suggests that exposure to violence (ETV) and violence‐related distress may cause or worsen asthma. Indeed, violence‐related distress may affect asthma pathogenesis through direct effects including abnormal responses to catecholamines and glucocorticoid therapy, and altered immune responses resulting in airway inflammation. Violence‐related distress may also affect asthma through indirect effects such as decreased physical activity and weight gain.We previously showed that ETV is associated with asthma in a high‐risk population (Puerto Ricans), in whom ETV is also associated with methylation of a CpG site in the promoter of the gene for the pituitary adenylate cyclase activating polypeptide 1 type 1 receptor (ADCYAP1R1) in white blood cells. Moreover, we reported that such methylation is associated with childhood asthma in Puerto Ricans.Based on previous results, we hypothesized that ETV and violence‐related distress would be linked to asthma through airway epithelial methylation of genes regulating autonomic, neuroendocrine, and immune responses. To examine this hypothesis, we carried out a epigenome‐wide association study (EWAS) of ETV or chronic stress measures and nasal (airway) epithelial methylation in 487 Puerto Rican participants (aged 9 to 20 years) in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study [EVA‐PR]). We evaluated four measures of ETV and chronic stress in children (ETV scale, gun violence, and perceived stress) and their mothers (perceived stress). Linear regression was used for each of the EWASs, with CpGs as dependent variables and the violence or stress scale as a predictor, adjusting for age, sex, principal components, and latent factors. We then selected the top 100 CpGs (by P‐value) associated with each scale in EVA‐PR. Since no replication cohort had data on stress or violence, we conducted a meta‐analysis of the selected CpGs and atopic asthma using data from EVA‐PR and two other cohorts (Project Viva and PIAMA).Three CpGs (in SNN, PTPRN2,and LINC01164) were associated with maternal stress or gun violence (P=1.28 to 3.36 ×10‐7), but not with atopic asthma, in EVA‐PR. In a meta‐analysis of three cohorts, which included the top CpGs associated with stress/violence measures in EVA‐PR, 12 CpGs (in STARD3NL, SLC35F4, TSR3, CDC42SE2, KLHL25, PLCB1, BUD13, OR2B3, GALR1, TMEM196, TEAD4 and ANAPC13) were associated with atopic asthma at FDR‐P< 0.05. PLCB1 has been associated with bronchodilator response and is differentially expressed in children with treatment‐resistant asthma compared with children with controlled persistent asthma or healthy controls.Pending confirmation in longitudinal studies, our results suggest that nasal epithelial methylation markers associated with ETV and chronic stress may be linked to atopic asthma in youth.