The α7 nicotinic acetylcholine receptor and the acute stress response: maternal genotype determines offspring phenotype

Abstract

α7 Nicotinic acetylcholine receptors (α7nAchRs) modulate immune activation by suppressing production of pro-inflammatory cytokines in peripheral immune cells. α7nAchRs also modulate inhibitory output in the hippocampus, which provides input to key circuits of the HPA axis. Therefore, the α7 nicotinic acetylcholine receptor gene (CHRNA7) may be associated with cortisol stress response. Polymorphisms in the CHRNA7 promoter decrease its expression and may dampen the cholinergic response, leading to an increase in inflammation. Increased inflammation may change the intrauterine environment, altering neuroendocrine development in the offspring. Maternal CHRNA7 genotype could affect an offspring's HPA regulation via reprogramming in utero. Patients with allergic disorders have a differential cortisol response to stress. This study utilized samples collected from a cohort of 198 adolescents in a previous study of atopic disorders, who demonstrated a disturbance in HPA response associated with atopy. Salivary cortisol samples collected from the adolescents after a series of laboratory procedures and DNA samples collected from the adolescents and their parents were used for further analysis. DNA samples were genotyped for allelic variation in the CHRNA7 promoter. Genetic association analyses with the cortisol levels were performed in the adolescents. Maternal genotype influences were investigated for the CHRNA7 gene. We also included maternal and child atopy diagnosis as covariates in determining cortisol levels and tested for association of CHRNA7 to atopy. Polymorphisms in the CHRNA7 promoter were associated with lower cortisol levels after a small laboratory stress. Our findings also show that although the child's CHRNA7 genotype affects stress response, the maternal genotype has a stronger influence on cortisol release after stress in male offspring. These effects were independent of atopy status.

Fig. 1

Effect of maternal child CHRNA7 polymorphisms on cortisol levels after the blood draw stressor. A. Pattern of cortisol levels during the test day, AM and PM groups. Average cortisol levels decreased at each time point, except at the blood draw time point. PM levels were significantly lower compared to the AM group at baseline, after the blood draw, and after the interview (2 sample T-test). AM group: N = 95; PM group: N = 87 *p < 0.05 ***p < 0.001. B. Cortisol levels during the test day stratified by child genotype (AM group only). On average, adolescents with a normal CHRNA7 promoter (allele 1, red) had a rise in cortisol following the blood draw stressor while those who carried a promoter polymorphism (Allele 2, blue) did not. *p = 0.023. C. Effect of child CHRNA7 polymorphisms on cortisol levels after the blood draw stressor (AM Group). Male and female adolescents with allele 1 had significantly higher salivary cortisol levels after the blood draw compared with those with allele 2. Allele 1, N = 40 females and 32 males; Allele 2, N = 12 females and 11 males. *p < 0.05. D. Effect of maternal CHRNA7 polymorphisms on child cortisol levels after the blood draw (AM Group). Males whose mothers carried a polymorphism had significantly lower cortisol levels compared to those whose mothers had normal promoters. Females were not affected by maternal genotype. Maternal Allele 1, N = 37 females and 35 males; Allele 2, N = 15 females and 8 males. ***p < 0.001. Error bars are one standard error from the mean.