FKBP5 polymorphisms as vulnerability to anxiety and depression in patients with advanced gastric cancer: A controlled and prospective study

doi:10.1016/j.psyneuen.2012.02.017

Psychoneuroendocrinology

Volume 37, Issue 9, September 2012, Pages 1569-1576

https://doi.org/10.1016/j.psyneuen.2012.02.017 Get rights and content

Summary

Cancer patients, who have to adapt to a long treatment process with multiple stressful events, show various stress responses. Genetic components may contribute to individual differences in stress response and risk for development of stress-related psychiatric problems. The present study aimed to investigate the influence of FK506 binding protein 5 (FKBP5) gene polymorphisms regulating the hypothalamic–pituitary–adrenal (HPA) axis on individual distress levels in cancer patients faced with similar stressful situation. The present study used a prospective design to elucidate predictors of distress.

A total of 130 patients (90 males, 40 females) who were newly diagnosed with advanced gastric cancer and supposed to receive first-line chemotherapy were initially assessed, and a six-week follow-up assessment occurred for 93 patients (63 males, 30 females) after two cycles of chemotherapy. Distress levels and coping patterns were measured by the Hospital Anxiety and Depression Scale (HADS) and Mini-Mental Adjustment to Cancer (Mini-MAC) scale. For genetic factors, three single nucleotide polymorphisms of FKBP5 rs1360780, rs9296158 and rs9470080 were genotyped.

For HADS-anxiety, FKBP5 rs9296158 had a significant group-by-time interaction (p = 0.015), and rs9470080 and rs1360780 had a marginally significant interaction (p = 0.023, p = 0.038, respectively). For HADS-depression, rs9470080 and rs9296158 had a marginally significant group-by-time interaction (p = 0.026, p = 0.032, respectively). In addition, a step-wise linear regression analysis showed that FKBP5 rs9470080 and rs9296158 were significant predictors of anxiety and depression after prolonged stress exposure in cancer patients.

Our findings indicate that the genetic factors regulating the HPA axis such as FKBP5 gene polymorphisms may play a crucial role in anxiety and depression following prolonged stress exposure.

Introduction

People respond to stress differently, even in the same stressful situation (Andreassi, 2007). The determinants of these individual stress responses are not clearly defined. According to the diathesis-stress model (Zubin and Spring, 1977), there are genetic or biological predispositions and environmental stressors that combine to manifest as abnormal behaviors and mental illness. Considerable evidence also supports the concept that susceptibility to stress-related psychiatric disorders such as mood and anxiety disorders is due to interactions between genetic vulnerability and environmental factors (Kendler, 1995, Stein et al., 1999, Sullivan et al., 2000).

Because the biological aspect of stress response is characterized by regulation of the hypothalamic–pituitary–adrenal (HPA) axis (Chrousos and Gold, 1992, Johnson et al., 1992), genetic factors regulating the HPA axis may contribute to differences of individual HPA axis responses and vulnerability to stress-related psychiatric problems (Yehuda et al., 2009). In particular, genetic variants of FK506 binding protein 5 (FKBP5), the major regulatory protein of the HPA axis have received growing interest (Binder, 2009, Lekman et al., 2008, Roy et al., 2010). FKBP5, a co-chaperone of hsp90 is known to bind to the glucocorticoid receptors (GR) and modulate glucocorticoid sensitivity (Binder, 2009). A FKBP5 overexpression in New World Monkeys has been reported to be associated with GR insensitivity (Scammell et al., 2001). The variants of the FKBP5 gene located on chromosome 6p21 facilitate altered GR sensitivity, leading to decreased efficiency of the negative feedback in the HPA axis and dysregulated stress response in healthy individuals (Binder et al., 2004). A recent cohort study showed that FKBP5 is a promising gene target for depression and treatment response (Lekman et al., 2008). In addition, a study of post-traumatic stress disorder (PTSD) suggested that FKBP5 gene variants moderate the effects of early life stress on the stress hormone system, which thus contributes to adult PTSD symptoms (Binder et al., 2008). These findings suggest that FKBP5 gene variants may contribute to dysregulated biological responsivity and lead to vulnerable phenotypes such as depression and anxiety in the face of long-lasting stressors.

Although there have been numerous studies of stress response after chronic stress exposure, most of them were conducted using animal models and in vitro experiments. As it is not easy to examine responses to similar stressors in humans, the role of biological factors underlying human stress responses and psychopathology is not well understood thus far. In humans, one of the most distressing events is being diagnosed with and undergoing treatment for a life-threatening disease such as cancer. From first diagnosis to chemotherapy during treatment courses, cancer patients have to suffer a long process of adaptation to multiple stressful events (Andersen et al., 1994, Courtens et al., 1996, Derogatis et al., 1983, Glass, 1983). Because patients with an incurable advanced gastric cancer have a short survival of only 7–9 months even with chemotherapy (Cervantes et al., 2008), they cannot help but think of their fate and face stressful situations, thus showing high stress responses.

The purpose of the present study was to elucidate the influence of FKBP5 gene polymorphisms regulating the HPA axis on distress levels in advanced gastric cancer patients faced with similar stressful situations. A prospective design was used to improve our knowledge about predictors of psychological distress. Initial psychological distress in patients newly diagnosed with advanced gastric cancer was examined and their distress level was measured at a six-week follow-up after two cycles of chemotherapy.

Section snippets

Participants

The participants included 130 patients (90 males, 40 females) diagnosed with advanced non-resectable gastric cancer from the outpatient clinic in the Yonsei Cancer Center and oncology clinic at Gangnam Severance Hospital. All participants in the present study were included in a clinical trial of specific combination chemotherapy, which was the randomized phase II trial of S-1 or capecitabine in combination with oxaliplatin. Participants were newly diagnosed with metastatic or recurrent

Characteristics of participants

Among 130 participants, 93 patients (63 males, 30 females) were available for follow-up assessment. Their mean age was 58.1 years (SD = 11.6). They had undergone two cycles of chemotherapy for a clinical trial (S-I + Oxalipaltin (N = 48) or Capecitabine + Oxalipaltin (N = 45)). At the initial assessment, most participants had a score of 0 (11.8%) or 1 (86.0%) for their ECOG performance status. Their initial mean scores of HADS-anxiety and HADS-depression were 6.5 (4.0) and 7.7 (4.1), respectively, and

Discussion

The present study prospectively investigated the influence of FKBP5 gene polymorphisms on stress responses in patients newly diagnosed with advanced gastric cancer. FKBP5 rs9470080 and rs9296158 showed a group-by-time interaction for HADS-anxiety and HADS-depression. For rs1360780, there was a marginally significant group-by-time interaction in HADS-anxiety (p = 0.038). In addition, FKBP5 rs9470080 and rs9296158 were significant predictors of HADS-anxiety and HADS-depression scores after six

Role of the funding sources

None.

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgement

The present study was performed collaterally to the phase II clinical study of Oxaliplatin in combination with S-1 versus Capecitabine in patients with metastatic or recurrent gastric cancer (NCT00985556).

References (30)

A. Ayres et al.
Influence of mood and adjustment to cancer on compliance with chemotherapy among breast cancer patients
J. Psychosom. Res.
(1994)
A. Cervantes et al.
The treatment of advanced gastric cancer: current strategies and future perspectives
Ann. Oncol.
(2008)
E.O. Johnson et al.
Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis
Neurosci. Biobehav. Rev.
(1992)
M. Lekman et al.
The FKBP5-gene in depression and treatment response—an association study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Cohort
Biol. Psychiatry
(2008)
J.G. Scammell et al.
Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates
Gen. Comp. Endocrinol.
(2001)
R. Yehuda et al.
Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks
Biol. Psychiatry
(2009)
B.L. Andersen et al.
A biobehavioral model of cancer stress and disease course
Am. Psychol.
(1994)
J.L. Andreassi
Heart activity and behavior. II. Stress, emotions, motivation, personality, social factors, brain interactions, and conditioning
Psychophysiology: Human Behavior and Physiological Response
(2007)
J.C. Barrett et al.
Haploview: analysis and visualization of LD and haplotype maps
Bioinformatics
(2005)
E.B. Binder et al.
Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment
Nat. Genet.
(2004)

E.B. Binder et al.

Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults

JAMA

(2008)

E.B. Binder

The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders

Psychoneuroendocrinology

(2009)

G.P. Chrousos et al.

The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis

JAMA

(1992)

E.S. Costanzo et al.

Coping and quality of life among women extensively treated for gynecologic cancer

Psychooncology

(2006)

A.M. Courtens et al.

Longitudinal study on quality of life and social support in cancer patients

Cancer Nurs.

(1996)

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Citation Excerpt :
Likewise, rs1329600 in DAPK1 is not associated with depression in these patients. Kang et al.56 reported the association of two SNPs in FKBP5 (rs9296158 and rs9470080) with depression severity among gastric cancer patients. They demonstrated that both SNPs showed a genotype by time interaction effect with depression level in these patients.
Cancer patients suffer from a repertoire of symptoms, including such psychological and psychiatric symptoms as anxiety, depression, and posttraumatic stress. Exploration of genetic factors that modify the risk and severity of these symptoms may facilitate the development of personalised care plans for managing these symptoms. This review aims to provide an overview on the variations in genes that may contribute to the occurrence and severity of anxiety, depression, and posttraumatic stress disorder (PTSD) among cancer patients. Literature search was performed in nine English and Chinese electronic databases, and extracted data are presented narratively. The reporting quality of the included studies was assessed using selected items of The STrengthening the REporting of Genetic Association (STREGA) checklist. Twenty-nine studies were included in the review. Most studies involved breast cancer patients, while patients of other cancer types appeared to be understudied. A number of studies reported the association between genes involved in inflammatory pathways and depression and anxiety. Other genes found to show associations with anxiety, depression, and PTSD among cancer patients are those involved in neurotrophic signalling, serotonergic signalling, regulation of stress response, antioxidation, dopamine catabolism and cellular apoptosis, despite some inconsistencies in findings between studies. Our review highlighted a need for further research for enhancing our knowledge on the association between genetic variations and anxiety, depression, and PTSD of patients of various cancer types. Future studies examining such associations in patients of various cancers should utilise standardised instruments for outcome assessments and stratify the patients based on their age for analysis.
Allele-specific DNA methylation level of FKBP5 is associated with post-traumatic stress disorder
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Harmful alcohol use was defined as a score of ≥12 using the validated Korean version of AUDIT (Lee et al., 2000). rs1360780 polymorphism on the FKBP5 locus was selected, based on previous studies on FKBP5 (Binder et al., 2008; Fujii et al., 2014; Kang et al., 2012; Klengel et al., 2013). The genotyping method and primer pairs for the assay were identical to those in our previous study on stress responses in cancer patients (Kang et al., 2012).
FK506-binding protein 5 (FKBP5) binds to glucocorticoid receptors and modulates glucocorticoid sensitivity. The FKBP5 gene has been implicated in the dysregulation of human stress responses, contributing to the risk and treatment response of stress-related disorders. The present study examined whether epigenetic changes in FKBP5 are associated with chronic post-traumatic stress disorder (PTSD) status in the context of FKBP5 genetic variation (rs1360780 polymorphism) among male veterans exposed to combat trauma.
Korean male veterans who served on active duty during the Vietnam War were categorized into 2 groups: with PTSD (n = 123) and without PTSD (n = 116). The genotype of FKBP5 rs1360780 and DNA methylation levels of two CpG sites at the FKBP5 intron 7 region were assessed in peripheral blood. Analysis of covariance was performed to examine main and interaction effects of PTSD status and FKBP5 genotype on FKBP5 DNA methylation level, with age, trauma levels, and alcohol use as covariates.
A significant main effect of FKBP5 rs1360780 and PTSD and an interaction effect between genotype and PTSD status were found on mean FKBP5 DNA methylation level. The T allele of rs1360780 was associated with lower FKBP5 methylation level. In addition, the PTSD group showed significantly higher methylation than did the non-PTSD group among veterans carrying the risk T allele (n = 96), while no group difference was observed on methylation levels among veterans with the CC genotype (n = 143). Among veterans carrying the T allele, FKBP5 methylation levels were positively correlated with the severity of PTSD symptoms.
The present study demonstrated different FKBP5 methylation levels in PTSD depending on FKBP5 genetic variation among veterans exposed to combat trauma. The present finding suggests that the genetic and epigenetic modulation of FKBP5 is involved in the pathophysiology of PTSD. Further longitudinal research involving people exposed to trauma is required to understand causal relationships of FKBP5 in the development and recovery of PTSD.
Examining FKBP5 mRNA expression in human iPSC-derived neural cells
2017, Psychiatry Research
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Increased levels of FKBP5 protein inhibit GR activity, creating a short negative feedback loop whereby GR activation limits further GR activation (Binder, 2009; Zannas and Binder, 2014). Polymorphisms within a 100 kb haplotype block in FKBP5 that are tagged by the single nucleotide polymorphism (SNP) rs1360780 have been linked to a number of stress-related psychiatric conditions including PTSD, anxiety, depression, and addictive disorders (Binder et al., 2004, 2008; Lavebratt et al., 2010; Roy et al., 2010; Kang et al., 2012; Klengel et al., 2013; Huang et al., 2014; Levran et al., 2014; Jensen et al., 2015). For PTSD, childhood trauma, but not adult trauma, interacts with FKBP5 genotype to predict greater self-reported symptoms on the PTSD Symptom Scale (Binder et al., 2008), while for other stress-related disorders FKBP5 genotype has been reported to interact with both childhood and lifetime stressors (Zannas and Binder, 2014).
In peripheral blood leukocytes, FKBP5 mRNA expression is upregulated following glucocorticoid receptor activation. The single nucleotide polymorphism rs1360780 in FKBP5 is associated with psychiatric illness and has functional molecular effects. However, examination of FKBP5 regulation has largely been limited to peripheral cells, which may not reflect regulation in neural cells. We used 27 human induced pluripotent stem cell lines (iPSCs) derived from 20 subjects to examine FKBP5 mRNA expression following GR activation. Following differentiation into forebrain-lineage neural cultures, cells were exposed to 1 μM dexamethasone and mRNA expression of FKBP5 and NR3C1 analyzed. Results from the iPSC-derived neural cells were compared with those from 15 donor matched fibroblast lines. Following dexamethasone treatment, there was a 670% increase in FKBP5 expression in fibroblasts, mimicking findings in peripheral blood-derived cells, but only a 23% increase in iPSC-derived neural cultures. FKBP5 rs1360780 genotype did not affect the induction of FKBP5 mRNA in either fibroblasts or neural cells. These results suggest that iPSC-derived forebrain-lineage neurons may not be an optimal neural cell type in which to examine relationships between GR activation, FKBP5 expression, and genetic variation in human subjects. Further, FKBP5 induction following GR activation may differ between cell types derived from the same individual.
Associations between the FKBP5 haplotype, exposure to violence and anxiety in females
2016, Psychoneuroendocrinology
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The epigenetic mechanisms behind G × E are not clear, however, it has been suggested that FKBP5 SNPs results in divergent chromatin conformations as well as interactions of long-range enhancers with the transcription starting site, influencing transcriptional activity of FKBP5 by GR-activation when triggered by childhood abuse (Klengel et al., 2013). The minor alleles of rs3800373, rs9296158 and rs9470080 have also been associated with PTSD when combined with high levels of childhood trauma (Binder et al., 2008; Xie et al., 2010), whereas the minor alleles of rs9296158 and rs9470080 have been shown to predict anxiety and depression after prolonged stress exposure in cancer patients (Kang et al., 2012). In addition, the minor alleles of rs3800373, rs9296158, rs9470080 and rs4713916, in combination with adverse life events, have been shown to predict depression in preschool children (Scheuer et al., 2016) and in adults (Zimmermann et al., 2011).
The gene that encodes the FK506-binding protein 5 (FKBP5) is regarded as a candidate for investigating how negative life events interact with a genetic predisposition to stress-related disorders, such as depression and anxiety. Given the role of FKBP5 as an important regulator of stress responses, we aimed to investigate if single-nucleotide polymorphisms (SNPs) in FKBP5—in the presence/absence of exposure to violence—are associated with symptoms of depression and anxiety. Data from two community-based samples of adolescents (n = 1705) and young adults (n = 1800) regarding ratings on depression, anxiety, exposure to violence and FKBP5 genotype were collected. A risk haplogenotype including the minor alleles of seven common SNPs in the FKBP5 (rs3800373, rs9296158, rs7748266, rs1360780, rs9394309, rs9470080 and rs4713916) conferred higher ratings on anxiety among females, but not males, in the presence of violence. Exposure to violence and female sex were associated with higher ratings on both depression and anxiety, with the exception of ratings on depression among young adults, on which sex had no effect. Ratings on depression were not associated with the haplogenotype. These findings may correspond to differences in the regulation of the HPA axis and with the higher vulnerability to anxiety in females.
Effects of chronic mild stress on behavioral and neurobiological parameters - Role of glucocorticoid
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Major depression is thought to originate from maladaptation to adverse events, particularly when impairments occur in mood-related brain regions. Hypothalamus–pituitary–adrenal (HPA) axis is one of the major systems involved in physiological stress response. HPA axis dysfunction and high glucocorticoid concentrations play an important role in the pathogenesis of depression. In addition, astrocytic disability and dysfunction of neurotrophin brain-derived neurotrophin factor (BDNF) greatly influence the development of depression and anxiety disorders. Therefore, we investigated whether depressive-like and anxiety-like behaviors manifest in the absence of glucocorticoid production and circulation in adrenalectomized (ADX) rats after chronic mild stress (CMS) exposure and its potential molecular mechanisms. The results demonstrate that glucocorticoid-controlled rats showed anxiety-like behaviors but not depression-like behaviors after CMS. Molecular and cellular changes included the decreased BDNF in the hippocampus, astrocytic dysfunction with connexin43 (cx43) decreasing and abnormality in gap junction in prefrontal cortex (PFC). Interestingly, we did not find any changes in glucocorticoid receptor (GR) or its chaperone protein FK506 binding protein 51 (FKBP5) expression in the hippocampus or PFC in ADX rats subjected to CMS. In conclusion, the production and circulation of glucocorticoids are one of the contributing factors in the development of depression-like behaviors in response to CMS. In contrast, the effects of CMS on anxiety-like behaviors are independent of the presence of circulating glucocorticoids. Meanwhile, stress decreased GR expression and enhanced FKBP5 expression via higher glucocorticoid exposure. Gap junction dysfunction and changes in BDNF may be associated with anxiety-like behaviors.
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FKBP5 polymorphisms as vulnerability to anxiety and depression in patients with advanced gastric cancer: A controlled and prospective study

Summary

Introduction

Section snippets

Participants

Characteristics of participants

Discussion

Role of the funding sources

Conflict of interest

Acknowledgement

J. Psychosom. Res.

Ann. Oncol.

Neurosci. Biobehav. Rev.

Biol. Psychiatry

Gen. Comp. Endocrinol.

Biol. Psychiatry

A biobehavioral model of cancer stress and disease course

Am. Psychol.

Heart activity and behavior. II. Stress, emotions, motivation, personality, social factors, brain interactions, and conditioning

Psychophysiology: Human Behavior and Physiological Response

Haploview: analysis and visualization of LD and haplotype maps

Bioinformatics

Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment

Nat. Genet.

Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults

JAMA

The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders

Psychoneuroendocrinology

The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis

JAMA

Coping and quality of life among women extensively treated for gynecologic cancer

Psychooncology

Longitudinal study on quality of life and social support in cancer patients

Cancer Nurs.