Polymorphism in CRHR1 gene affects the IL-1β levels in suicidal attempters

https://doi.org/10.1016/j.jpsychires.2016.11.009Get rights and content

Abstract

Approximately one million people commit suicide every year, being suicide attempts and ideation even more common. Changes in stress response and activation of the immune system have been associated with suicide risk. Here we investigated the interaction between immune system and HPA axis alterations in the suicide risk, looking for the influence of rs110402 CRHR1 SNP in the IL-1β levels according to suicide ideation and attempt. This study evaluated 171 subjects of which 15 had suicidal ideation, 20 had suicide attempt and 136 were controls. Genotyping was performed by real-time PCR and IL-1β levels were measured by ELISA. Our data showed that for each point increase in IL-1β levels the risk of suicide attempt increased 5% [relative risk = 1.05 (95% CI: 1.0–1.10)]. After sample stratification by rs110402 SNP genotypes, we observed that in subjects carrying the A allele the risk raised to 15% [relative risk = 1.15 (95% CI: 1.03–1.28)], suggesting an apparent effect modification. Thus, this study showed that alterations in CRHR1 gene were associated with higher levels of IL-1β, and increased risk for suicide, reinforcing the importance of multifactorial interactions of biological markers for psychiatric disorders.

Introduction

Approximately one million people commit suicide every year (WHO, 2013), being one of the ten leading causes of death worldwide (Bertolete and Fleischmann, 2002). Suicide ideation and attempt are even more common (Tondo et al., 2007), and identifying risk factors in patients with psychiatric disorders is an area of increasing public health concern. The etiology of suicidal behavior is complex in that genetic, psychological and environmental factors can play a role (Correa et al., 2004).

Neurobiological findings suggest that inflammation is a possible trigger for suicide behavior, independently of psychiatric disorders (Steiner et al., 2008). Studies have shown that an increase in pro-inflammatory cytokines is associated with the suicide behavior (Tonelli et al., 2008, Steiner et al., 2008), where higher levels of interleukine-1β (IL-1β) were linked to suicidal tendencies, including risk, attempt and completed suicide (Black and Miller, 2015). IL-1β is an endogenous signaling molecule released by macrophages and monocytes during the acute phase of the inflammatory response. This pro-inflammatory cytokine is capable of modulating cerebral functions during systemic and localized inflammation, acting as a critical mediator of adaptive response to stress (John and Buckingham, 2003) by stimulation of corticotrophin-releasing hormone (CRH) release (Gadek-Michalska and Bugajski, 2010, Goshen and Yirmiya, 2009, Lopez-Castejon and Brough, 2011). In turn, CRH via corticotrophin-releasing hormone receptors (CRHR) activate the hypothalamic-pituitary-adrenal axis (HPA), promoting subsequent release of cortisol.

Furthermore, HPA axis and the immune system communicate at multiple levels through the CRH, which can indirectly exert an anti-inflammatory effect via stimulation of cortisol release, and directly exerts a pro-inflammatory effect on immune cells promoting the secretion of cytokines as IL-1β (Karalis et al., 1991). In this context, consistent findings show that the direct pro-inflammatory effect of CRH is mediated for its CRHR1 receptor binding, which appears to be necessary for the development of local inflammation and direct paracrine effect on resident cells at the site of inflammation (Agelaki et al., 2002). However, data from modulation of immune system by CRHR is scarce in the literature, and require investigations.

Genetic variations of HPA axis could be related to the dysregulation on this axis and immune response, increasing vulnerability for psychiatric disorders and suicidal behavior (Domschke and Maron, 2013, Wasserman et al., 2008, Xiao et al., 2011, Szczepankiewicz et al., 2011). One of the most extensively studied polymorphisms in the CRHR1 gene is the rs110402, which has been associated with increased risk for seasonal pattern and early age of onset of the first depressive episode (Papiol et al., 2007), anxiety traits, as well as differences in cortisol response (Mahon et al., 2013). However, taking into account the hypothesis of HPA axis dysregulation in psychiatric disorders, little is known about the role of CRHR1 polymorphisms and suicide susceptibility. Thus, this study aim to investigate the interaction between immune system and HPA axis alterations in the suicide risk, looking for the influence of rs110402 CRHR1 SNP in the IL-1β levels according to ideation and attempt suicide.

Section snippets

Study design and participants

This cross-sectional study consisted of 171 individuals aged 18–35, enrolled from a population-based study carried out in the urban area of the city of Pelotas, Southern Brazil, between June 2011 to May 2013. Sample selection has been previously described (Moreira et al., 2015). Home visits were conducted in the morning when participants answered a standard questionnaire to collect sociodemographic information, life style, psychiatric medication, and comorbidities. The subjects were evaluated

Results

A total of 171 individuals were included in this study, with 136 controls, 15 participants with suicide ideation and 20 with suicide attempt. The sociodemographic and clinical characteristics according to suicide risk are compiled in Table 1. We found a significant association between the groups in relation to gender (p ≤ 0.030), diagnosis of mood disorder (p ≤ ≤0.001) and smoke (p ≤ 0.001), with higher prevalence of women, major depression and smoke in the groups of subjects with suicide

Discussion

Suicide risk etiology is known to be linked to inflammation, and immune response has been proven to be genetically influenced. Here, we speculate that genetic factors in immune dysfunction may be involved in the pathophysiology of suicide risk. Our data are in agreement with previous data, showing that IL-1β levels confers a risk for suicide attempt and that the A allele of rs110402 SNP in the CRHR1 gene increase in 3-fold the risk in those subjects.

The role of IL-1β in suicide risk is not well

Conflict of interest

All authors disclose no conflict of interest.

Contributors

Author Clarissa R Bastos contributed to the manuscript through her participation in genetic and biochemical experiments, data analysis, managed the literature searches and wrote the first draft of the manuscript. Marta Gazal and Carolina D. Wiener participated in the organization of data collection and Elisa analysis. Joice L. Costa performed the collection of blood samples and DNA extraction. Authors Luciana de A. Quevedo, Karen Jansen and Luciano D.M. Souza participated in the organization of

Acknowledgements

The authors are grateful to CNPq and FAPERGS for their research fellowships. The authors are grateful to CNPq and CAPES for their research fellowships. This study was partly funded by the FAPERGS (08/2009) and CNPq (PRONEX 10/0055).

References (44)

  • A. Pfennig et al.

    Hypothalamus-pituitary-adrenal system regulation and suicidal behavior in depression

    Biol. Psychiatry

    (2005)
  • P.H. Roseboom et al.

    Persistent corticotropinreleasing factor1 receptor desensitization and downregulation in the human neuroblastoma cell line IMR-32

    Brain Res. Mol. Brain Res.

    (2001)
  • J. Steiner et al.

    Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide

    J. Psychiatr. Res.

    (2008)
  • A. Szczepankiewicz et al.

    Glucocorticoid receptor polymorphism is associated with major depression and predominance of depression in the course of bipolar disorder

    J. Affect. Disord.

    (2011)
  • A.R. Tyrka et al.

    Interaction of childhood maltreatment with the corticotropin-releasing hormone receptor gene: effects on hypothalamic-pituitary-adrenal axis reactivity

    Biol. Psychiatry

    (2009)
  • S. Agelaki et al.

    Corticotropin-releasing hormone augments proinflammatory cytokine production from macrophages in vitro and in lipopolysaccharide-induced endotoxin shock in mice

    Infect. Immun.

    (2002)
  • Y.J. Ben-Efraim et al.

    Gene-environment interactions between CRHR1 variants and physical assault in suicide attempts

    Genes Brain Behav.

    (2011)
  • J.M. Bertolete et al.

    Suicide and psychiatric diagnosis: a worldwide perspective

    World Psychiatry

    (2002)
  • E.B. Binder et al.

    The CRF system, stress, depression and anxiety – insights from human genetic studies

    Mol. Psychiatry

    (2010)
  • R.G. Bradley et al.

    Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene

    Arch. Gen. Psychiatry

    (2008)
  • H. Correa et al.

    Familial suicide behaviour: association with probands suicide attempt characteristics and 5-HTTLPR polymorphism

    Acta Psychiatr. Scand.

    (2004)
  • K. Domschke et al.

    Genetic factors in anxiety disorders

    Mod. Trends Pharmacopsychiatri

    (2013)
  • Cited by (13)

    • The role of gene polymorphisms, and analysis of peripheral and central levels of interleukins in suicidal behavior: A systematic review

      2021, Journal of Affective Disorders
      Citation Excerpt :

      On the other hand, five studies measured levels of interleukins in CSF (Bay-Richter et al., 2015; Erhardt et al., 2013; Lindqvist et al., 2011; Lindqvist et al., 2009; Martinez et al., 2012); the main outcome reported was an increase of IL-6 in CSF associated with suicide, which was also linked with the severity of the method used (for instance, individuals with violent-SA had the higher levels of IL-6) (Bay-Richter et al., 2015; Lindqvist et al., 2011; Lindqvist et al., 2009). On the other hand, four articles that studied interleukins levels and genetic analysis (Bastos et al., 2017; Chang et al., 2019; Melhem et al., 2017) did not find an association with suicide attempt. Regarding the genetic analysis per se, we found six articles that evaluated interleukins in peripheral samples (Eftekharian et al., 2018; Kim et al., 2013b; Liu et al., 2011; Noroozi et al., 2018; Powers et al., 2016; Saiz et al., 2008).

    • An increase in IL-6 levels at 6-month follow-up visit is associated with SSRI-emergent suicidality in high-risk children and adolescents treated with fluoxetine

      2020, European Neuropsychopharmacology
      Citation Excerpt :

      Inflammatory processes have also been implicated in suicidality. Numerous studies have shown that abnormalities in cytokine levels comprise risk factors for SBs beyond their role in promoting depressive symptoms (Bastos et al., 2017; Black and Miller, 2015; Coryell et al., 2018; Ducasse et al., 2015; Ganança et al., 2016; Pandey, 2015; Serafini et al., 2013). For instance, mRNA and protein levels of IL-1β, IL-6, TNF-α, and lymphotoxin A were significantly increased in the prefrontal cortex of depressed individuals who died by suicide compared with controls (Pandey et al., 2018).

    View all citing articles on Scopus
    View full text