Original articleThe corticotropin-releasing hormone binding protein is associated with major depression in a population from Northern Sweden
Introduction
In the neurobiology of major depressive disorder (MDD), recent research has focused on the role of the hypothalamic-pituitary-adrenal (HPA) axis. More specifically, major depression has been associated with a hyperactivity of the HPA axis, probably driven primarily by hypersecretion of corticotropin releasing hormone (CRH) (Plotsky et al 1998). The dexamethasone-suppression test (DST) is a functional test of the HPA axis (Arana 1991). A number of depressed patients do not show normal suppression of cortisol secretion after administration of dexamethasone (DEX). The combined DEX/CRH test (Heuser et al 1994) shows higher sensitivity (90%) than the DST (20% to 50%). Pretreatment with DEX prevents a substantial release of adrenocorticotropic hormone (ACTH) and cortisol after additional administration of CRH in healthy individuals. In depressed patients, however, a paradoxically increased secretion of ACTH and cortisol is observed. Taken together, these data constitute substantial evidence for a dysfunction in HPA axis autoregulation in affective disorders.
The reactivity of the HPA axis can be influenced by genetic as well as environmental factors. It has been shown, in several species, that early adverse trauma can lead to persistent elevation in HPA axis reactivity Coplan et al 1996, Ladd et al 1996, Liu et al 1997. In women, childhood sexual abuse is an important early stressor that predisposes to dysregulation of the HPA axis and therefore probably for depression Weiss et al 1999, Heim et al 2000, Heim et al 2001. The liability to develop major depression is partly determined by genetic factors, with heritability estimates ranging from 48% to 75% (McGuffin et al 1996). In some families, a dysfunction of the HPA axis is transmitted as a genetic trait that increases the liability for depression. Holsboer et al (1995) found that in a number of cases, high-risk probands of patients with recurrent major depression share the HPA axis dysfunction with their affected relatives. In a follow-up study, it was shown that this dysregulation remains stable over a 5-year period (Modell et al 1998).
Many genes are possible functional candidates for the genetic trait of CRH hyperactivity. Most authors suggested that a genetic variation in the glucocorticoid and mineralocorticoid receptor genes, mediating the negative HPA axis feedback by cortisol, might be responsible (Plotsky et al 1998); however, the regulation of the level of free CRH after exposure to stress is also tightly regulated by the expression of CRH binding protein (CRH-BP) (Lombardo et al 2001). Corticotropin releasing hormone binding protein is a 37-kDa secreted glycoprotein that binds human CRH with an equal or greater affinity than the CRH receptor 1 (Vaughan et al 1995). Corticotropin releasing hormone binding protein is expressed in many regions of the brain, including layers II, III, V, and VI of the cerebral cortex; the dentate gyrus; and cornu amonnis (CA)1 and CA3 regions of the hippocampus and the amygdala (Potter et al 1992). It is also expressed in the anterior pituitary corticotrophs (Peto et al 1999). In vitro studies have shown that CRH-BP can block the CRH-mediated ACTH secretion from the anterior pituitary cells Peto et al 1999, Potter et al 1991, leading to the hypothesis that CRH-BP might act as a negative regulator of CRH activity in vivo. Lombardo et al (2001) found that acute stress increased the CRH-BP messenger RNA (mRNA) concentration by 20% in the basolateral amygdala, a system important in mediating stress, fear, and anxiety.
Studies from transgenic mice demonstrated that mice overexpressing CRH-BP show increased activity and slightly decreased anxiety (Burrows et al 1998), while CRH-BP knockout mice showed a significant increase in anxiogenic-like behavior (Karolyi et al 1999)
The aim of this study was to detect single nucleotide polymorphisms (SNPs) in the human CRH-BP gene occurring in the general population. Subsequently, the role of such variations in the liability to develop mood disorders was examined by performing association analysis in a sample of major depressive patients and healthy controls.
Section snippets
Subjects
The case-control sample consisted of 89 unrelated unipolar (UP) patients and 88 controls matched for age, gender, and ethnicity. In the patient group, the gender ratio was 55 female patients/34 male patients, and the mean age at inclusion was 69.7 ± 8.8 years. In the control group, the gender ratio was 54 female subjects/34 male subjects, and the mean age was 66.8 ± 11.5 years. The mean age at onset in the patient group was 37.9 ± 15.4 years. All patients and control subjects originated from
Validation of publicly available SNPs
Existing databases were consulted for known SNPs within the CRH-BP gene. The National Center for Biotechnology Information (NCBI) SNP database (http://www.ncbi.nlm.nih.gov/SNP/) and the HGBase variation database (http://www.hgbase.de/) contained 11 SNPs within the gene. Three of these were localized in repeat sequences, and for 2 other SNPs, no PCR product could be obtained. The other 6 SNPs were genotyped in 48 UP patients and 48 control subjects, and only 2 SNPs were polymorphic: rs1875999
Discussion
This study offers a systematic detection of SNPs in the CRH-BP gene and subsequent association analysis in a well-defined sample of UP patients and matched control subjects. Six SNPs and one deletion polymorphism were genotyped in the clinical sample.
No SNPs were detected in the exons of the CRH-BP gene. This might imply that the CRH-BP gene is under important selection pressure and therefore highly conserved. This is in concordance with the high conservation of this gene across species (e.g.,
Acknowledgements
We thank Lien Heyrman, Samira Bel-Kacem, Hubert Backhovens, and Dirk Van den Bossche for their excellent technical support. The project was funded in part by a research project of the Fund for Scientific Research Flanders (FWO) and a concerted action project of the University of Antwerp, Belgium.
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