Polygenic risk score of SERPINA6/SERPINA1 associates with diurnal and stress-induced HPA axis activity in children. (July 2018) - Utge, Siddheshwar
Highlights: In children with genetic risk for high blood cortisol levels in the morning, salivary cortisol levels decreased less from awakening to bedtime. In children with genetic risk for high blood cortisol levels in the morning, salivary cortisol levels increased in response to stress. Genetic risk for high blood cortisol levels in the morning associated with high diurnal salivary cortisol AUC and bedtime salivary cortisol. Of the 6 SNPs studied, rs7161521 ( SERPINA6 ) and rs4900229 ( SERPINA1 ) showed strongest links with the diurnal and stress-induced cortisol levels. Abstract: Purpose: Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood. Variation in genes SERPINA6 encoding for CBG, SERPINA2 and SERPINA1 (serpin family A member 6, 2, and 1) have been shown to influence morning plasma cortisol and CBG in adults. However, association of this genetic variation with diurnal and stress-induced salivary cortisol remain unknown. This study aims to investigate the effect of genetic variation in SERPINA6 / 2 / 1 loci on diurnal and stress-induced salivary cortisol in children. Methods: We studied 186, 8-year-old children with genome-wide genotyping. We generated weighted polygenic risk score (PRS) based on 6 genome-wide significant SNPs (rs11621961, rs11629171, rs7161521, rs2749527, rs3762132, rs4900229) derived from the CORNET meta-analyses. Salivary cortisol was measured across one day and in response to the Trier Social Stress Test for Children (TSST-C). Results: Mixed models, adjusted for covariates, showed that the PRS x sampling time interactions associated with diurnal ( P < 0.001) and stress-induced ( P = 0.009) salivary cortisol. In the high PRS group (dichotomized at median) the diurnal salivary cortisol pattern decreased less from awakening to bedtime than in the low PRS group (standardized estimates of sampling time −0.64 vs. −0.73, P < 0.0001 for both estimates). In response to stress, salivary cortisol increased in the high PRS group while it remained unchanged in the low PRS group (standardized estimates of sampling time 0.12, P = 0.015 vs. −0.06, P = 0.16). These results were mainly driven by minor alleles of rs7161521 ( SERPINA6 ) and rs4900229 ( SERPINA1 ). Conclusions: Genetic variation in SERPINA6/2/1 loci may underpin higher hypothalamic-pituitary-adrenocortical axis activity in children.