Stress, ADCYAP1R1, and Childhood Asthma. No Sigh of Relief

Children with asthma in the United States continue to experience suffering and diminished quality of life (1). Despite decades of research, the precise genetic and environmental factors giving rise to asthma and its phenotypic characteristics have remained elusive. Children from Puerto Rico in particular have a greater asthma prevalence (8–49%) (2) and disease burden compared with children from other ethnic groups (2, 3). The exposure to early-life psychosocial stress (PSS) (4, 5) and an increased susceptibility to PSS among Puerto Ricans (6) may contribute to these disparities. These themes of PSS and asthma-related genetic predisposition are presented in a series of interesting analyses in this issue of the Journal, presented by Brehm and colleagues (pp. 47–56) (7). More broadly, research has clearly demonstrated that children exposed to PSS more often suffer from a variety of long-term health problems ranging from cancer to depression to asthma (8). Sources of PSS often include child neglect or abuse, extreme poverty, and family violence (9), which appear to disrupt the coordinated development of the central nervous system and the neuroendocrine and immune systems (9). Specifically, the hypothalamic–pituitary–adrenal axis, which is important in regulating stress, appears to be dysfunctional in humans born into and experiencing high PSS (10). PSS clearly increases the risk for asthma diagnosis (4) and can worsen existing disease (11). In fact, before asthma was understood as an inflammatory disease of the airways, “asthma nervosa” was largely seen as a somatic manifestation of stress and of the psyche. Maimonides first described the important role of emotion and psychology in asthma (12). Later, Sir William Osler agreed with this view and described asthma as a “neurotic affliction” (13). The gene ADCYAP1R1, which encodes for pituitary adenylate cyclase–activating polypeptide type I receptor (PAC1) and binds pituitary adenylate cyclase activating peptide, may play a role in stress and asthma among Puerto Ricans. ADCYAP1R1 functions along with the hypothalamic–pituitary–adrenal axis to regulate stress responses and has been associated with risk for post-traumatic stress disorder (14), childhood anxiety, and childhood asthma (15). Recently, several of the current authors found that children exposed to violence had greater DNA methylation of ADCYAP1R1 and that this greater methylation was also associated with asthma risk. Few previous studies have examined the role of genetic and molecular mechanisms linking PSS and asthma outcomes, and the recent results linking PSS, asthma, and ADCYAP1R1 are important but require replication and further study. The study performed by Brehm and colleagues presented here provides exciting new information about these links (7). They assessed whether stress or ADCYAP1R1 variation was associated with bronchodilator response (BDR) in children with asthma. BDR is important because it associates with clinical outcomes, airway inflammation, and response to inhaled corticosteroid therapy (16). The researchers performed a cross-sectional analysis of 6- to 14-year-old children with physician-diagnosed asthma from Puerto Rico. Replicate cohorts included similar-aged children from Rhode Island and Puerto Rico and a nonasthmatic cohort of children with reduced FEV1/FVC (to address nonadherence as a potential confounder). They estimated child stress stemming from violence during the preceding 6 months (measured using the Checklist of Children’s Distress Symptoms questionnaire), maternal stress (measured using the Perceived Stress Scale), and a composite “household stress” score. Spirometry (before and 15 minutes after appropriate bronchodilation) and DNA analysis were performed. The researchers found that children in the highest-stress quartiles in the primary and replicate cohorts displayed a significantly diminished percentage BDR compared with children with lower stress. Interestingly, high maternal stress had an even greater negative effect on BDR than did child stress. However, BDR was lowest among children who had both high stress themselves and had mothers with high stress (i.e., high household stress). These children had a BDR that was more than 10% lower than that of children without either high child or maternal stress, which is likely to be clinically meaningful. Next, common single-nucleotide polymorphism (SNPs) near ADCYAP1R1 were interrogated for association with reduced BDR. Six of 106 SNPs were found to be significant (P < 0.05) and were further tested in six appropriate replication cohorts. One SNP (rs34548976) was found to be highly associated with reduced BDR after correction for multiple testing. Using publically available data, the investigators further showed that the same rs34548976 SNP is associated with increased ADCYAP1R1 (PAC1) expression in both human lung and brain. The investigators then posed the question of whether this SNP in ADCYAP1R1 could cause reduced BDR mediated by greater anxiety leading to reduced ADRB2 expression. They found that in unstimulated CD4+ T cells from children and adults with asthma, rs34548976 was associated with reduced ADRB2 expression. However, it is unclear whether ADCYAP1R1-related BDR reductions are a result of reduced airway smooth muscle (ASM) ADRB2 expression, as ADCYAP1R1 is not expressed in ASM. BDR also can be reduced in children with greater airway collapsibility and closure after ASM relaxation (which could be affected by stress and ADCYAP1R1). However, the authors propose the more likely explanation for reduced BDR being from neurohormonal mechanisms under conditions of stress leading to ADRB2 down-regulation in ASM. Using functional magnetic resonance imaging data from adult African American women, the investigators showed that two copies of rs34548976 associated with greater connectivity between the amygdala and insula, a pathway that is influential in anxiety and dyspnea. Last, they showed that the rs34548976 SNP showed effect modification on BDR by child stress in those within the highest-stress group. Taken together, these inquiries are an important contribution to understanding how childhood stress in the setting of a genetic predisposition affects asthma pathogenesis. Future longitudinal studies will help establish whether stress antedates methylation changes and how acute versus chronic stress at different developmental ages affect asthma symptom control, exacerbations, and lung function over time. These intricate scientific findings are also of major public health significance, as they serve to underscore the importance of policies that support a safe and healthy family and community environment. Household stress is a modifiable risk factor our professions can help address. Protection of children from toxic stress by a nurturing adult caregiver backed by a supportive public health system is likely to protect millions of children from future disease.