A polymorphism in the regulatory region of the corticotropin-releasing hormone gene in relation to cortisol secretion, obesity, and gene-gene interaction

In recent years, a considerable body of evidence has emerged regarding the pathogenic role of cortisol in abdominal obesity. The regulation of the cor ticotropin-releasing hormone (CRH) gene might play an essential role becaus e it is the primary hypothalamic neuropeptide involved in the control of ad renal secretion of cortisol. Therefore, we examined the hypothalamic-pituit ary-adrenal function by repeated salivary samples for the assessment of cor tisol as well as other endocrine, anthropometric, metabolic, and circulator y variables in middle-aged Swedish men (n = 284). With the restriction enzy me XmnI, a variant in the 5'-flanking region of the CRH gene was identified (T255G). The observed genotype frequencies were 89.9% and 9.7% for T/T and T/G, respectively. Only 1 subject was homozygous for the rare allele (0.4% ; G/G). The results showed that the XmnI polymorphism of the CRH gene is no t associated with an altered cortisol-secretory pattern or sensitivity to g lucocorticoids or with obesity and its related metabolic and circulatory pe rturbations. However, when the interaction effect between a previously desc ribed TthlllI glucocorticold-receptor gene polymorphism and the present Xmn I CRH polymorphism was investigated, the cortisol levels before and during physiologic stress and the total diurnal cortisol secretion were significan tly increased among subjects who were carriers for both variants. From thes e results, we conclude that an abnormal production rate of the CRH gene pro duct in the presence of an inadequate glucocorticoid receptor density might lead to elevated cortisol levels. Copyright (C) 2001 by W.B. Saunders Comp any.