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