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