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SAT-1 -1415T/C Polymorphism and Suicidal Behavior

Info: 3118 words (12 pages) Dissertation
Published: 11th Dec 2019

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Tags: MedicalPsychologyMental Health

Abstract:

Background:

There is a growing interest in the potential role of polyamines in the pathophysiology depression and suicidal behavior. In particular, the expression of SAT-1 (the gene coding for polyamine rate-limiting catabolic enzyme) seems to be reduced in some brain samples from people who committed suicide. However, there is some controversy regarding the role of SAT-1 342A/C SNP (rs6526342) and other potentially functional genetic polymorphisms in a suicide.

Both acute and chronic stress has been linked to suicide attempts, and early life events may increased the risk of suffering from adult depression and suicidal behavior, which has been linked to hypothalamus-pituitary-adrenal (HPA) system deregulation. Polyamines are involved in the stress response.

The aim of the present study was to examine the association between the SAT-1 -1415T/C SNP (rs1960264) and suicidal attempts. This particular SNP has been previously linked to anxiety disorders in males, but, to date, there is no available data about this SNP in suicidal behavior.

Methods:
A case-control design was used in order to compare the genotypes for the SAT-1 -1415T/C SNP between non-completed suicidal patients (n= , __ females and __ males) and healthy controls (n=___, __ females and __ males).

Abbreviations:

AMD-1- Adenosyl-methyonin-decarboxylase-1

HPA -Hypothalamus-pituitary-adrenal

MAO – Monoamine oxydase

OATL-1 – Ornithin-amino-transferase-1

ODC- ornithin-decarboxylase

PAO- polyamine oxydase

PRE- Polyamine-responsive element

SAT-1 -Spermidine/spermine N1-acetyltransferase-1

SAT-2 – Spermidine/spermine N1-acetyltransferase-2

SMS-  spermin-synthase

SNP- Single nucleotide polymorphism

VPFC- ventral prefrontal cortex

Introduction

Several studies suggest that polyamines may be involved in mood disorders and suicidal behavior (Fiori and Turecki, 2008). The expression of polyamine´s rate-limiting catabolic enzyme (SAT-1, Spermidine/spermine N1-acetyltransferase-1) may be reduced in VPFC (ventral prefrontal cortex) (Guipponi et al., 2008; Sequeira et al., 2006) and posterior cyngulate gyrus of patients who committed suicide (more intensely in depressed than in non-depressed subjects) (Sequeira et al., 2007). Sequeira proposed that this reduction could be explained by the fact that a smaller frequency of the hyperfunctional allele rs6526342A can be found among suicide completers (Sequeira et al., 2006). Nevertheless, Guipponi could not demonstrate the involvement of any potential cis-acting loci controlling SAT-1 gene expression (neither rs6526342 nor rs17286006), and concluded that the reduction of SAT-1 mRNA in VPFC found in suicide committers may not be linked to methylation status on SAT-1´s promoter region (Guipponi et al., 2008).

Other studies have shown variable results regarding the connection of polyamine system with depression and suicidal behaviour. Serum PAO (polyamine oxydase) activity seemed to be increased in patients that suffered from severe depression and normalized in those who responded to ECT (electro-convulsive therapy) (Dahel et al., 2001). Moreover, increased SAT-2 (Spermidine/spermine N1-acetyltransferase-2) and OATL-1 (Ornithin-amino-transferase-1) in non-depressed suicide completers and raised brain SMS (spermin-synthase) among suicide completers (both with and without depression) have been reported (Sequeira et al., 2007). However, others could not find a significant change of SAT-1, ODC (ornithin-decarboxylase) or AMD1 (Adenosyl-methyonin-decarboxylase), or polyamine levels in hippocampus or frontal cortex from patients that had previously suffered from schizophrenia, depressive disorders or who had committed suicide (Gilad et al., 1995), or in the immunoreactivity to ODC in the enthorhinal cortex of depressed patients (Bernstein and Muller, 1999).

Both acute and chronic stress has been linked to suicide attempts (Conner et al., 2007). Early life events may increased the risk of suffering from adult depression, suicidal ideation and attempts (particularly in serotonin transporter 5HTTLPR short-allele carriers) (Caspi et al., 2003; Currier and Mann, 2008; Gibb et al., 2006; Roy et al., 2007). Adverse child rearing may increase the chance of future violent, antisocial, impulsivity-related conducts and suicidal behavior in those subjects carrying hypofunctional MAO alleles (Currier and Mann, 2008; Foley et al., 2004; Haberstick et al., 2005; Reif et al., 2007). Indeed, individuals suffering from bipolar disorder with a familial liability for suicidal behavior and exposed to physical and/or sexual abuse during childhood are at a greater risk of attempting suicide and have a more impaired course of illness compared to those subjects with either only one or none of these risk factors (Carballo et al., 2008).

Stress-related conditions, impulsivity, aggression and suicidal behaviour have been related to HPA (Hypothalamus-pituitary-adrenal) system deregulation (De, V et al., 2007; Pfennig et al., 2005; Swaab et al., 2005). Firstly, suicidal depressed patients show lower adrenocorticotrophin and cortisol response in the combined dexametasone/CRH test, and lower hormone levels, specially in recent suicide attempters (Pfennig et al., 2005). Secondly, a significant association of CRHR1 (corticotrophin releasing hormone receptor 1) gene rs4792887 SNP to suicide male attempters exposed to low levels of stress has been reported (Wasserman et al., 2007), and haplotype variation at the CRHR2 locus may also be associated with suicidal behaviour (De, V et al., 2007). Finally, cortisol levels in major depressive episodes with comorbid post-traumatic stress disorder seem to be reduced (Oquendo et al., 2003).

Polyamines participate in the biological response to stress (Fiori and Turecki, 2008; Vaquero-Lorenzo et al., 2008). Hence, physical, chemical or emotional stress elicits a significant increase in polyamine contents in many organs (particularly in brain regions involved in fear-conditioning, like amygdala and hippocampus). The magnitude of this effect depends directly on the intensity and duration of the stressful stimuli (Gilad and Gilad, 2003; Hayashi et al., 2004; Rhee et al., 2007). Besides, HPA system may be linked to polyamine metabolism, as ACTH (adrenocorticotrophin) is the main enhancer of the polyamine´s rate-limiting biosynthetic enzyme ODC in the adrenal glands (Bastida et al., 2007). Recently, SAT-1 rs1960264 SNP has been associated with anxiety disorders in a male caucasian spanish sample (Vaquero-Lorenzo et al., 2008).

This background prompted us to investigate the potential association between the SAT-1 -1415T/C SNP (rs1960264) and suicidal attempts. A case-control design was used in order to compare the genotypes for this SNP between suicidal attempters and healthy controls. Due to its proximity to the polyamine responsive element (PRE) and to the recognition sites for the transcription factors acting on the promoter region of SAT-1 (Tomitori et al., 2002), different allelic variants of SAT-1 -1415T/C (rs1960264) could potentially have some influence on the risk of committing a suicidal attempt.

Conocer si el genotipo SAT-1 -1415 T/C influye:

  1. intento autolítico
  2. letalidad de los intentos
  3. en el grado de impulsividad de los sujetos
  4. antecedentes de maltrato o early life events
  5. exposición reciente a estrés

Materials and methods

Suicide attempters (n=__, females and males) and healthy blood donors (n=  females and  males) were recruited at three general hospitals in Madrid, Spain. All patients included were Spanish Caucasians.

All participants gave written informed consent after a complete description of the study. The whole research was developed in compliance with the Code Ethics of the World Medical Association (Helsinki´s Declaration) and the standards established by the Institutional Review Board and granting agency.

DSM-IV diagnoses for psychiatric patients were provided using a brief structured psychiatric interview, the Mini International Neuropsychiatric Interview version 4.4 (MINI 4.4) (Sheehan et al., 1998). The General Health Questionnaire-12 (GHQ-12) (Lobo et al., 1986) was used as a screening test to detect psychopathology in the control group. Those individuals with scores above the cut off point were excluded from the analyses.

Genotype analysis

Genetic analysis was performed following the method previously described by our group (Vaquero-Lorenzo et al., 2008). Genomic DNA was extracted from peripheral blood samples collected from participants. PCR amplification of a 298-bp fragment from the promoter region of the SAT-1 gene, containing the PRE and the SAT-1 -1415T/C SNP, was carried out. The target region was amplified, the resultant PCR fragments were digested with restriction enzyme Msp I, and finally separated by electrophoresis ethidium bromide agarose gels. Then gels were scanned using ultraviolet light. Restriction fragments of 188 and 110 bp revealed the presence of allele C of the SAT-1 -1415T/C SNP, while allele T would have prevented the Msp I cut. However, different genotypes were checked with ABI PRISM 370 sequencing equipment, at Centro Nacional de Investigaciones Oncológicas (CNIO).

Statistical analysis

χ2 tests were calculated in order to compare genotype frequencies in  psychotic patients, non-psychotic psychiatric patients and healthy controls. Statistical analyses were carried out using the Statistical Package for Social Sciences (SPSS version 12.0).

Results

Discussion

The present study ……..significant association between the SAT-1-1415T/C polymorphism and suicidal attemps.

Several authors had previously linked to depression and suicidal behavior, with an increased frequency of SAT-1 342C allele among male franco-canadian suicide completers (Sequeira et al., 2006). Interestingly, SAT-1 342A/C polymorphism may have a significant influence upon the expression rate of SSAT-1 in the brain.

Recently, a positive association between SAT-1 -1415T/C polymorphism and anxiety has been demonstrated by our group (Vaquero-Lorenzo et al., 2008).

Some limitations should be considered. The statistical power in our study

other interesting dbSNPs at the promoter region of SAT-1 gen should be evaluated….

Some data was collected retrospectively…we used a semi-structured interview in order to assess the risk factors…

In conclusion, ……..our study explores an interesting physiopathological target for psychosis and other mental disorders. Future studies should examine other functional genotypes of polymorphisms on the SAT-1 gene or different genes encoding proteins regulating the polyamine metabolic pathway.

Tables

APUNTES:

Indeed, his group used 53 unrelated lymphoblastoid cell lines from the CEPH collection to try and test whether or not those SNPs could have some impact on SAT-1´s expression rate.

Although serotonergic system has been consistently related to the physiopathology of mood disorders and suicidal behavior, there is a growing interest in other potential targets that could be implicated in its pathophysiology.

SAT-1 promoter…, which is a embedded in a CpG island of 669bp with 59 CpG sites

Natural polyamines (putrescine, spermidine and spermine) are low molecular weight positively charged aliphatic molecules involved in many physiological functions such as cell growth, cell differentiation and apoptosis {Seiler, 2005 9415 /id}, oxidative stress response {Takano, 2005 630 /id;Belle, 2004 9916 /id}, immunity {Seiler, 1994 120 /id}, and the regulation of energy and calcium homeostasis in mitochondria {Salvi, 2004 9537 /id}. In the brain polyamines are mainly stored in astrocytes and synaptic vesicles, though they may act on a variety of receptors situated on the surface of glia and neurons {Takano, 2005 9532 /id;Masuko, 2003 622 /id}. 

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