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

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 CRH promoter were previously found to be associated with altered CRH promoter activity and physiological reactions. Functional characterization of three CRH promoter haplotypes have been performed in vitro using a reporter gene assay under different stimulation conditions. Furthermore, 232 healthy subjects were genotyped and the influence of CRH 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. In vitro, CRH 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. In vivo, CRH haplotype 2 carriers showed significant higher baseline blood pressure (p = .002) and blood pressure after SeCPT (p < .001), but did not differ in cortisol levels. This study provides converging evidence for the importance of CRH promoter variants on physiological stress response parameters.