Genetic Variants and the Cortisol Response in Children: An Exploratory Study.

OBJECTIVE: We examined genomic variation potentially associated with the cortisol stress response in children having a painful medical procedure. DESIGN: Children 4-10 years old having a peripheral intravenous line inserted provided saliva samples for evaluation of the cortisol response as a biological measure of distress: two on the day of the procedure and two at home on a nonstressful day for comparison values. Children and biological parents also provided samples for genotyping of variants with known or suspected association with the cortisol stress response. Analysis included child-only association and family-based transmission disequilibrium tests (TDTs). RESULTS: Genotype and phenotype data on the cortisol stress response were available from 326 children for child-only association analyses and 376 complete family trios for TDTs. Children were 50% female, an average of 7.5 years old, and mostly (83%) White/non-Hispanic. We identified four single-nucleotide polymorphisms (SNPs) potentially associated with the cortisol stress response: rs1176744 ( HTR3B), rs10062367 ( CRHBP), rs634479 ( OPRM1), and rs8030107 ( NTRK3). Family-based analysis identified a two-SNP haplotype in HTR1B suggestive for association with the cortisol response (rs6296, rs11568817). Allelic TDTs identified rs7897947 ( NFKB2) as potentially related to cortisol response. CONCLUSIONS: Findings provide preliminary evidence for genes potentially important in cortisol response to an acute stressor in children in the serotonin, dopamine, and brain-derived neurotrophic factor pathways, the hypothalamic-pituitary-adrenal axis, and the inflammatory response. Combined with analyses of related phenotypes and clinical data, these results could help identify patients at increased risk of adverse responses to painful medical procedures who might benefit from tailored interventions.