Stress and Treatment Response in Puerto Rican Children With Asthma

Stress and Treatment Response in Puerto Rican Children With Asthma

This study aims to first determine whether high child stress leads to reduced response to common treatmenIs for asthma (inhaled corticosteroids and short-acting bronchodilators), and then to identify DNA methylation differences leading to stress-induced treatment resistance among children with asthma.

Puerto Rican (PR) and African American children share a disproportionate burden from asthma in the U.S. The investigators have demonstrated that in PR children, a variety of psychological stressors are associated with worse asthma outcomes. Puerto Rican children also have reduced response to bronchodilators (short-acting inhaled β2-agonists, the most commonly used medication for asthma worldwide). The investigators have recently shown that high child stress is associated with reduced response to short-acting inhaled β2-agonists (bronchodilator response or BDR) in PR and non-PR children with asthma, and our preliminary results also implicate genetic and epigenetic (DNA methylation) variation in genes involved in stress responses (e.g., ADCYAP1R1) on asthma and BDR. Moreover, external in vitro experiments show that high stress leads to reduced expression of the genes for the β2-adrenergic receptor (ADRB2) and the glucocorticoid receptor (NR3C1) in white blood cells of children with asthma. While it is known that stress reduces BDR, it is not known whether this can be prevented by treatment with inhaled corticosteroids (ICS), or whether stress reduces response to ICS in vivo. Moreover, the research community has very limited knowledge of the genetic or epigenetic mechanisms underlying treatment resistance in stressed children. On the basis of novel preliminary results, the investigators hypothesize that chronic stress reduces response to inhaled corticosteroids (ICS) and BDR in PR and African American children with asthma, and that these effects are mediated by altered methylation of genes regulating responses to stress, corticosteroids and BDR. To test this hypothesis, the investigators will first determine whether increased stress leads to reduced response to ICS or BDR (even after treatment with ICS) in 300 PR and African American children with asthma (Aim 1). The investigators will then test for association between high child stress and genome-wide DNA methylation in respiratory (nasal) epithelium in 550 Puerto Rican and African American children with asthma (Aim 2). Next, the investigators will examine whether methylation changes in the top 100 genes identified in Aim 2 are associated with response to ICS or BDR in 300 to 550 PR and African American children with asthma (Aim 3a). Finally, the investigators will assess the effects of methylation changes identified in Aim 3a on gene expression (Aim 3b). This proposal should determine whether and how psychosocial stress leads to reduced response to common treatments for asthma control (ICS) and relief of asthma symptoms (short-acting inhaled β2-agonists) in a high-risk group (Puerto Rican and African American children).

Inclusion Criteria:

• Physician-diagnosed asthma
• BDR ≥8%99 or (if BDR<8%) increased airway responsiveness to methacholine (PD20 <16.81 umol)
• Four Puerto Rican grandparents
• Steroid naïve (no treatment with ICS, nasal, or oral corticosteroids in the prior 4 weeks)
• Parental consent and child's assent to participate in the study

Exclusion Criteria:

• Chronic disease (i.e. respiratory, liver, cardiac, renal, neurologic) other than asthma
• Severe asthma, as evidenced by: a) intubation for asthma at any time, or b) ≥3 hospitalizations or ≥6 visits to the emergency department/urgent care in the previous year, or c) chronic/continuous need for medications other than single controller therapy [ICS or leukotriene inhibitors] and short-acting β2-agonists
• Current smoking or former smoking if ≥5 pack-years
• Inability to perform acceptable spirometry
• FEV1 <60% of predicted