Modulation of cortisol responses to the DEX/CRH test by polymorphisms of the interleukin-1beta gene in healthy adults

Sasayama Daimei, Hori Hiroaki, Iijima Yoshimi, Teraishi Toshiya, Hattori Kotaro, Ota Miho, Fujii Takashi, Higuchi Teruhiko, Amano Naoji, Kunugi, Kunugi Hiroshi

Description

Recently, hypothalamus-pituitary-adrenal (HPA) axis function assessed with the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test has been shown to be associated with response to antidepressant treatment. A polymorphism (rs16944) in the interleukin-1beta ( IL-1β ) gene has also been reported to be associated with the medication response in depression. These findings prompted us to examine the possible association between IL-1β gene polymorphisms and HPA axis function assessed with the DEX/CRH test. Methods DEX/CRH test was performed in 179 healthy volunteers (45 males: mean age 40.5 ± 15.8 years; 134 females: mean age 47.1 ± 13.2 years). Five tagging single nucleotide polymorphisms (SNPs) of IL-1β gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) were selected at an r 2 threshold of 0.80 with a minor allele frequency > 0.1. Genotyping was performed by the TaqMan allelic discrimination assay. A two-way factorial analysis of variance (ANOVA) was performed with the DEX/CRH test results as the dependent variable and genotype and gender as independent variables. To account for multiple testing, P values < 0.01 were considered statistically significant for associations between the genotypes and the cortisol levels. Results The cortisol levels after DEX administration (DST-Cortisol) showed significant associations with the genotypes of rs16944 ( P = 0.00049) and rs1143633 ( P = 0.0060), with no significant gender effect or genotype × gender interaction. On the other hand, cortisol levels after CRH administration (DEX/CRH-Cortisol) were affected by gender but were not significantly influenced by the genotype of the examined SNPs, with no significant genotype × gender interaction. Conclusions Our results suggest that genetic variations in the IL-1β gene contribute to the HPA axis alteration assessed by DST-Cortisol in healthy subjects. On the other hand, no significant associations of the IL-1β gene polymorphisms with the DEX/CRH-Cortisol were observed. Confirmation of our findings in futures studies may add new insight into the communication between the immune system and the HPA axis.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2011
• Nombre de lectures: 12
• Langue: English

Extrait

Sasayama et al. Behavioral and Brain Functions 2011, 7:23
http://www.behavioralandbrainfunctions.com/content/7/1/23
RESEARCH Open Access
Modulation of cortisol responses to the DEX/CRH
test by polymorphisms of the interleukin-1beta
gene in healthy adults
1,2* 1,4 1,3 1 1 1 1Daimei Sasayama , Hiroaki Hori , Yoshimi Iijima , Toshiya Teraishi , Kotaro Hattori , Miho Ota , Takashi Fujii ,
1 2 1,4Teruhiko Higuchi , Naoji Amano and Hiroshi Kunugi
Abstract
Background: Recently, hypothalamus-pituitary-adrenal (HPA) axis function assessed with the combined
dexamethasone (DEX)/corticotropin releasing hormone (CRH) test has been shown to be associated with response
to antidepressant treatment. A polymorphism (rs16944) in the interleukin-1beta (IL-1b) gene has also been reported
to be associated with the medication response in depression. These findings prompted us to examine the possible
association between IL-1b gene polymorphisms and HPA axis function assessed with the DEX/CRH test.
Methods: DEX/CRH test was performed in 179 healthy volunteers (45 males: mean age 40.5 ± 15.8 years; 134
females: mean age 47.1 ± 13.2 years). Five tagging single nucleotide polymorphisms (SNPs) of IL-1b gene
2
(rs2853550, rs1143634, rs1143633, rs1143630, rs16944) were selected at an r threshold of 0.80 with a minor allele
frequency > 0.1. Genotyping was performed by the TaqMan allelic discrimination assay. A two-way factorial analysis
of variance (ANOVA) was performed with the DEX/CRH test results as the dependent variable and genotype and
gender as independent variables. To account for multiple testing, P values < 0.01 were considered statistically
significant for associations between the genotypes and the cortisol levels.
Results: The cortisol levels after DEX administration (DST-Cortisol) showed significant associations with the
genotypes of rs16944 (P = 0.00049) and rs1143633 (P = 0.0060), with nont gender effect or genotype ×
gender interaction. On the other hand, cortisol levels after CRH administration (DEX/CRH-Cortisol) were affected by
gender but were not significantly influenced by the genotype of the examined SNPs, with no significant genotype
× gender interaction.
Conclusions: Our results suggest that genetic variations in the IL-1b gene contribute to the HPA axis alteration
assessed by DST-Cortisol in healthy subjects. On the other hand, no significant associations of the IL-1b gene
polymorphisms with the DEX/CRH-Cortisol were observed. Confirmation of our findings in futures studies may add
new insight into the communication between the immune system and the HPA axis.
Background [4,5]. In experimental animals, exogenous
administraRecent studies have provided several lines of evidence tions of IL-1b have produced depressive-like symptoms,
implicating the pro-inflammatory cytokine interleukin- which were attenuated by treatment with
antidepres1beta (IL-1b) in the etiology and pathophysiology of sants [6,7]. Furthermore, administration of the IL-1
depression. Studies investigating peripheral levels of IL- receptor antagonist has ameliorated the stress-like
1b have reported elevated concentrations of IL-1b in effects in cellular and behavioral models [8,9], making it
patients with major depression [1-3] and dysthymia a possible candidate for therapeutic targets.
A few studies have examined genetic polymorphisms
* Correspondence: [e-mail] of the IL-1b gene for association with depression.
1Department of Mental Disorder Research, National Institute of Neuroscience, Although no significant allelic or genotypic differences
National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502,
have been found between patients with depression andJapan
Full list of author information is available at the end of the article
© 2011 Sasayama et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.Sasayama et al. Behavioral and Brain Functions 2011, 7:23 Page 2 of 8
http://www.behavioralandbrainfunctions.com/content/7/1/23
healthy controls [10-12], three studies have consistently Because gender effects on measures of HPA axis
funcshown that the G allele of rs16944 in the IL-1b gene is tion have been previously reported [32,35], a two-way
associated with poor response to antidepressant factorial analysis of variance (ANOVA) was performed
treatment [10,13,14]. This evidence suggests that genetic with the DEX/CRH test results as the dependent
variregulation of inflammatory processes mediated by IL-1b able and genotype and gender as independent variables
is involved in the pathophysiology of depression and to determine the possible interaction effects between the
resistance to antidepressant treatment. polymorphisms and gender.
Alterations in the hypothalamic-pituitary-adrenal
(HPA) axis have been well-documented in depression Methods
and related psychopathological conditions (reviewed by Subjects
[15,16]). We have also reported heightened HPA axis in Subjects were 179 adult healthy volunteers (45 males:
major depression and its normalization after treatment mean age 40.5 ± 15.8 years, 134 females: mean age 47.1
as assessed with the combined dexamethasone (DEX)/ ± 13.2 years) recruited from the community through
corticotropin releasing hormone (CRH) test [17,18]. The advertisements in free local information magazines and
relationship between alteration of the HPA axis activa- by our website announcement. Most of the subjects
tion and immune alterations in depression has been were from our previous sample, in which the
relationdescribed in several studies [19-21]. The increased ship between stress, sleep, and HPA function was
examexpression of pro-inflammatory cytokines is thought to ined [36-38]. All subjects were biologically unrelated
lead to the progression of the immune response and Japanese individuals without current or past history of
activation of the HPA axis [22-24]. In particular, IL-1b psychiatric treatment, and were screened with a direct
is considered to play an important role in the HPA axis contact interview by a research psychiatrist using the
alteration. A significant positive correlation between Japanese version of the Mini International
Neuropsymitogen-induced IL-1b production and post-DEX corti- chiatric Interview (M.I.N.I.) [39,40] to rule out any axis
sol values have been reported, suggesting that IL-1b I psychiatric disorders. Participants were excluded if
hypersecretion may contribute to HPA axis hyperactivity they had prior medical histories of central nervous
[25]. Animal studies have further demonstrated that the system disease or severe head injury, if they met the
crirelease of CRH stimulated by IL-1 is involved in the teria for substance abuse or dependence or mental
retarHPA activation [26-28]. dation, if they had received glucocorticoid treatment,
Intriguingly, a number of studies have shown that the psychotropic treatment, antihypertensive medications,
DEX/CRH test may be a predictor for response to oral contraceptives, or estrogen replacement therapies in
antidepressant treatment. Ising et al [29] found that the previous month, or if they suffered from any
inflamhigher cortisol level after DEX administration prior to matory, infectious, or systemic immune diseases, based
CRH stimulation was associated with a favorable treat- on self-reports, at the time of assessment. The study
ment outcome. Two recent studies showed that protocol was approved by the ethics committee at the
response to antidepressant treatment was more favor- National Center of Neurology and Psychiatry, Japan.
able in depressive patients whose peak cortisol levels After description of the study, written informed consent
during the DEX/CRH test were reduced after the initia- was obtained from every subject.
tion of the treatment [30,31]. Further, in the study by
Binder et al [32], antidepressant response was associated Genotyping
with higher cortisol response to the DEX/CRH test in Five tagging single nucleotide polymorphisms (SNPs) in
male, but not female, patients. It is plausible that the a region 1 kilobase (kb) upstream to 1 kb downstream
DEX/CRH test and the antidepressant response are of the IL-1b gene (rs2853550, rs1143634, rs1143633,
related, since antidepressants may exert their clinical rs1143630, rs16944) were selected by Haploview 4.2 [41]
effects, at least in part, by reducing the activity of the using Japanese and Chinese population in the HapMap
2HPAsystem[33,34].ThefactthatboththeHPAaxis SNP set (release 22), at an r thresholdof0.80witha
activity and the IL-1b gene polymorphism influence the minor allele frequency greater than 0.1. Genomic
response to antidepressants further supports the organization and linkage disequilibrium structure of the
evidence of reciprocal relationships between the HPA IL-1b gene are shown in Figure 1. Genomic DNA was
system and IL-1b. prepared from the venous blood according to standard
These previous findings prompted us to examine the procedures. The SNPs were genotyped using the
Taqpossible association of polymorphisms in the IL-1b and Man 5’-exonuclease allelic discrimination assay. Thermal
the HPA function. In the present study, the relationship cycling conditions for polymerase chain re