ADCYAP1R1 and Asthma in Puerto Rican Children

Abstract

Rationale: Epigenetic and/or genetic variation in the gene encoding the receptor for adenylate-cyclase activating polypeptide 1 (ADCYAP1R1) has been linked to post-traumatic stress disorder in adults and anxiety in children. Psychosocial stress has been linked to asthma morbidity in Puerto Rican children. Objectives: To examine whether epigenetic or genetic variation in ADCYAP1R1 is associated with childhood asthma in Puerto Ricans. Methods: We conducted a case-control study of 516 children ages 6-14 years living in San Juan, Puerto Rico. We assessed methylation at a CpG site in the promoter of ADCYAP1R1 (cg11218385) using a pyrosequencing assay in DNA from white blood cells. We tested whether cg11218385 methylation (range, 0.4-6.1%) is associated with asthma using logistic regression. We also examined whether exposure to violence (assessed by the Exposure to Violence [ETV] Scale in children 9 yr and older) is associated with cg11218385 methylation (using linear regression) or asthma (using logistic regression). Logistic regression was used to test for association between a single nucleotide polymorphism in ADCYAP1R1 (rs2267735) and asthma under an additive model. All multivariate models were adjusted for age, sex, household income, and principal components. Measurements and Main Results: Each 1% increment in cg11218385 methylation was associated with increased odds of asthma (adjusted odds ratio, 1.3; 95% confidence interval, 1.0-1.6; P ¼ 0.03). Among children 9 years and older, exposure to violence was associated with cg11218385 methylation. The C allele of single nucleotide polymorphism rs2267735 was significantly associated with increased odds of asthma (adjusted odds ratio, 1.3; 95% confidence interval, 1.02-1.67; P ¼ 0.03). Conclusions: Epigenetic and genetic variants in ADCYAP1R1 are associated with asthma in Puerto Rican children.

Stress and Bronchodilator Response in Children with Asthma

“…We found no association between ADCYAP1R1 SNP rs2267735 (previously associated with PTSD [9,11,63,64] and asthma [13]) and BDR. SNP rs34548976 is not in LD with rs2267735, and is thus a novel risk variant for both anxiety and BDR.…”

“…Yet another unanswered question is whether dysfunction of the pituitary adenylate cyclase-activating polypeptide 1 (PACAP-PAC1) pathway explains potential effects of stress on the b 2 -adrenergic receptor (9,10). This is relevant, because the gene encoding the PACAP 1 receptor type 1 (ADCYAP1R1) has been previously implicated in posttraumatic stress disorder (PTSD) (9,11), anxiety (12), and asthma (13).…”

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

“…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.…”

Asthma in childhood

“…It is also known that children from Puerto Rico have lower bronchodilator response and greater asthma morbidity than children from other ethnic groups, an observation that may be explained by either the presence of allelic variants in ADRB2 [43] or increased psychosocial stress in this population [44]. The gene encoding the pituitary adenylate cyclase-activating polypeptide 1 (PACAP 1) receptor type 1 (ADCYAP1R1) has been previously implicated in anxiety [45] and asthma [46], but it is actually unknown whether dysfunction of the PACAP 1 pathway explains the potential effect of stress on the ADRB2. In order to evaluate whether stress or ADCYAP1R1 variation was associated with reduced bronchodilator response in children with asthma, BREHM et al [47] performed a cross-sectional study in 351 asthmatic children living in Puerto Rico and in a replication study cohort (RIPRAC).…”