Promoter haplotypes of the corticotropin-releasing hormone encoding gene modulate the physiological stress response <i>in vitro</i> and <i>in vivo</i>

The corticotropin-releasing hormone (CRH) is a neuropeptide mediating stress responses. CRH exerts effects via the hypothalamus pituitary adrenal axis as well as immediate effects on the sympathetic-adrenal-medullary system. Genetic variants of the <i>CRH</i> promoter were previously found to be associated with altered <i>CRH</i> promoter activity and physiological reactions. Functional characterization of three <i>CRH</i> promoter haplotypes have been performed <i>in vitro</i> using a reporter gene assay under different stimulation conditions. Furthermore, 232 healthy subjects were genotyped and the influence of <i>CRH</i> haplotypes on basal parameters such as post-awakening cortisol and blood pressure as well as on stress reactivity measured after socially evaluated cold pressor test (SeCPT) was investigated. <i>In vitro, CRH</i> haplotype 2 showed the highest promoter activity under baseline conditions and after forskolin stimulation compared with other haplotypes. Forskolin treatment resulted in a two fold increase of haplotype 2 promoter activity compared with the baseline condition. Cell line-dependent promoter activation was found after hydrocortisone treatment. <i>In vivo</i>, <i>CRH</i> haplotype 2 carriers showed significant higher baseline blood pressure (<i>p</i> = .002) and blood pressure after SeCPT (<i>p</i> CRH promoter variants on physiological stress response parameters.