Sylwia Fudalej

Possible association between suicide committed under influence of ethanol and a variant in the AUTS2 gene

Background rs6943555 in AUTS2 has been shown to modulate ethanol consumption. We hypothesized that rs6943555 might be associated with completed suicide. Methods We genotyped rs6943555 in 625 completed suicides and 3861 controls using real-time TaqMan Allelic Discrimination Assay. All individuals were Polish Caucasians. Results We detected an association between suicide and rs6943555 A allele (OR = 1.17, P = 0.018 for allelic comparison, OR = 1.24, P = 0.013 for dominant, and OR = 1.18, P = 0.020 for co-dominant model of inheritance). The association remained significant after adjusting for age and gender (co-dominant: P = 0.002 and dominant model: P = 0.001). After stratifying suicides according to blood ethanol concentration (BAC≤ 20 mg/dl and BAC > 20 mg/dl) the association remained significant only for cases who committed suicide under influence of alcohol (co-dominant: OR  =  1.37, P = 0.004 and dominant model: OR = 1.45, P = 0.006). To validate this finding we genotyped another cohort of 132 cases. We reproduced the association between rs6943555 A allele and suicide under influence of ethanol (allelic comparison: OR = 1.55, P = 0.023; co-dominant : OR = 1.54, P = 0.031; dominant model: OR = 1.84, P = 0.015). Analyzing pooled suicides with BAC >20 mg/dl (N = 300) we found the association of rs6943555 A allele not only vs. controls (allelic OR = 1.41, P = 0.00029) but also vs. cases with BAC ≤ 20 mg/dl (N = 449, allelic OR = 1.33, P = 0.019). Conclusions In our study rs6943555 A allele is associated with suicide committed after drinking ethanol shortly before death. The rs6943555 A allele may be linked to adverse emotional reaction to ethanol, which could explain the association with lower consumption in general population as well as the predisposition to suicide under influence of ethanol.

Angiotensin-Converting Enzyme Polymorphism and Completed Suicide: An Association in Caucasians and Evidence for a Link with a Method of Self-Injury

Background/Aims: An association between the II genotype of the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism and suicide was found among Japanese men. Our purpose was to replicate this finding in Caucasians and explore other putative genotypic associations among suicides. Methods: The ACE genotypes were studied by a 2-stage PCR method in 150 completed suicides and 165 age- and sex-matched controls. Results: We found an increase in the frequency of the ACEI allele among male victims of suicide compared to male controls (odds ratio, OR = 1.69, p < 0.006), female suicides (OR = 2.01, p = 0.006) and pooled controls (OR = 1.77, p = 0.001). Analysis of genotype distribution showed that the codominant model had the best fit (p = 0.7) whereas the recessive model could be rejected (p = 0.04). Among males we found an association between the number of the ACE I allele and the method of suicide: OR = 17.98, pcorrected = 0.00003, for jumping from a height; OR = 0.36, pcorrected = 0.048, for hanging. We also observed a trend for a negative effect of the number of copies of the ACE I allele on prevalence of depression (OR = 0.36, p = 0.013) and a trend for an effect on age at death (p = 0.021). Conclusions: Our results suggest that low ACE activity associated with the I allele is a risk factor for suicide, especially in a subset of males. This may be of concern given the widespread use of drugs lowering ACE activity.

Analysis of four genes involved in the neurodevelopment shows association of rs4307059 polymorphism in the cadherin 9/10 region with completed suicide.

Background: We hypothesized that DNA variants affecting neurodevelopment such as rs4307059 (CDH10/CDH9), rs930752 (NRXN1), rs6265 (BDNF) or rs10868235 (NTRK2) may predispose to completed suicide. Methodology: We used a case-control two-stage approach based on a discovery cohort (557 cases and ∼550 controls) and replication cohort (159 cases and 186 controls). The suicides were ascertained as consecutive cases autopsied at the Department of Forensic Medicine, Medical University of Warsaw, Poland. Results: In the discovery cohort we found an association between suicide and the CC genotype in the rs4307059 polymorphism (OR 1.64, p = 0.012). The trend for an overrepresentation of the CC homozygotes among suicides was replicated in the second cohort (OR 1.97, p = 0.056). Analysis in the pooled cohorts showed that rs4307059 CC was associated with completed suicide (OR 1.71, p = 0.002) also after Bonferroni correction (pcor. = 0.024). In an exploratory search for genotype-phenotype correlation we found that males with the rs4307059 CC genotype committed suicide earlier than those with CT/TT genotypes (p = 0.049). Conclusions: The CC genotype of rs4307059 located in the region between CDH9 and CDH10 is associated with completed suicide in a Polish cohort.

No association between MTHFR C677T polymorphism and completed suicide

MTHFR C677T polymorphism (rs1801133) was associated with numerous psychiatric conditions but no prior study investigated whether it predisposes to completed suicide. We typed rs1801133 in 692 suicide victims and 3257 controls representative of a Polish adult population (the WOBASZ cohort). Although we had a power of 0.8 to detect (at alpha 0.05) an allelic OR=1.19, we did not find significant difference among suicides vs. controls in the prevalence of the MTHFR 677T allele (OR=1.02, p=0.759) or the TT genotype (OR=1.01, p=0.926). Since among controls we found an association between TT and depression defined by Beck Depression Inventory (BDI, OR=1.61, p=0.049) we also compared suicides with controls without signs of depression (BDI ≤ 11) but found no association (OR=1.0, p=0.976). Analyses within suicides showed trends (not significant after Bonferroni correction) for correlations between the dose of the T allele and age at death among males and blood ethanol concentration among females, who committed suicide under the influence of alcohol. We conclude that MTHFR C677T polymorphism is not a risk factor for completed suicide. The sex-specific trends for correlations between rs1801133 and age at death, and blood ethanol concentration should be studied further.

Inverse Association between Obesity Predisposing FTO Genotype and Completed Suicide

The A allele of rs9939609 in the FTO gene predisposes to increased body mass index (BMI) and obesity. Recently we showed an inverse association between the obesity related A allele of rs9939609 and alcohol dependence which was replicated by others. Since this finding raises a possibility that FTO may be associated with other psychiatric phenotypes, we aimed to examine association of rs9939609 with completed suicide. We genotyped rs9939609 in 912 suicide victims and 733 controls using TaqMan approach. We observed an inverse association between suicide and the rs9939609 A allele (OR = 0.80, P = 0.002, Pcor = 0.006) with genotype distribution suggesting a co-dominant effect. Given the link between alcoholism and suicide under influence of alcohol reported in Polish population, confounding by alcohol addiction was unlikely due to apparently similar effect size among cases who were under influence of ethanol at the time of death (OR = 0.76, P = 0.003, N = 361) and those who were not (OR = 0.80, P = 0.007, N = 469). The search for genotype-phenotype correlations did not show significant results. In conclusion, our study proves that there is an inverse association between rs9939609 polymorphism in FTO gene and completed suicide which is independent from association between FTO and alcohol addiction.

Manganese-induced Parkinsonism among ephedrone users and drug policy in Poland.

A recent governments prohibition policy in Poland was partially successful with a reduction of the synthetic drugs market and a decrease in drug-related poisoning mortality rates. However, a new threatening trend is observed. There are a growing number of individuals in Poland and other European countries using legal pharmaceuticals containing ephedrine or pseudoephedrine to produce stimulants. This case report describes a history of a male patient with polysubstance dependence who administered self-designed ephedrone derived from Sudafed using potassium permanganate. He revealed significant clinical symptoms of manganese-induced parkinsonism. No effective treatment could be recommended. Awareness of this severe neurological and social consequences should lead to prevention efforts including educational programs and initiatives reducing availability of the legal medications containing ephedrine or pseudoephedrine. More research is needed to enhance our knowledge about manganism and potential treatment regimens.

Physical pain and impulsivity in alcohol-dependent patients

Abstract Background: Physical pain and impulsivity are considered to be prevalent and significant factors that influence the course of alcohol dependence. The aim of the study was to investigate relationships between different dimensions of impulsivity and the current experience of physical pain in individuals entering alcohol treatment. Method: A sample of 366 (73.5% men and 26.5% women) DSM-IV alcohol-dependent subjects was recruited in alcohol treatment centers in Poland. The study sample was divided into a ‘mild or no pain’ group (65.6%) and a ‘moderate or greater pain’ group (34.4%). Levels of impulsivity were measured by the stop-signal task as well as the total and subscale scores of the Barratt Impulsiveness Scale (BIS-11). Results: The experience of physical pain was significantly associated with higher levels of impulsivity as measured by both total BIS-11 scores and longer stop reaction times. Physical pain remained as independent correlate of behavioral impulsivity (stop reaction time) and the BIS-11 subscale of attentional impulsivity while controlling for other variables. An additional analysis revealed that BIS-11 scores were not associated with stop reaction times. Conclusions: Physical pain is an independent correlate of both subjectively reported and objectively measured levels of impulsivity. Therapeutic interventions aimed at reducing pain in alcohol-dependent individuals should be studied to evaluate their impact on improving attention and behavioral control.

Somatic Comorbidity and Other Factors Related to Suicide Attempt Among Polish Methadone Maintenance Patients.

Objectives:Fatal and nonfatal suicide attempts are far more common in opioid-dependent individuals than in the general population. More research is needed to understand the specific risk factors for suicidal behaviors in this patient population, particularly outside of the United States and Western Europe. This study investigated the correlates of suicide attempts among Polish patients in methadone maintenance treatment and interpreted results in the context of findings from other countries. Methods:The study was based on a sample of 240 individuals recruited from a methadone maintenance clinic in Poland. Participants were interviewed using standardized measures. Results:Consistent with studies in other countries, sexual abuse, depression, alcohol dependence, and impulsivity were associated with suicide attempt. Additionally, those patients with somatic comorbidity had an increase in odds (odds ratio = 2.6) of suicide attempt. Conclusions:The results of our study suggest a potential benefit to treatment approaches that address somatic concerns of methadone-maintenance patients. More research is needed to identify, assess, and understand possible cultural and regional differences between opioid-dependent populations to better tailor prevention strategies.

COMT and BDNF Gene Variants Help to Predict Alcohol Consumption in Alcohol-dependent Patients.

Background: The neurobiology of alcohol dependence (AD) involves alterations in neurotransmitters and the stress response. We hypothesized that an interaction between functional variants of dopaminergic and neurotrophic genes may influence drinking in AD. Methods: The relationship between alcohol consumption and single-nucleotide polymorphisms, Val66Met in the brain-derived neurotrophic factor (BDNF), and Val158Met in the catechol-O-methyltransferase (COMT), was analyzed among 281 alcohol-dependent individuals. Results: Individuals carrying both the COMT Met158Met genotype and the BDNF Val66Val genotype drank more than those with other variants of these genes (P = 0.039). Those who had a family history of AD also drank more than those without a family history (P = 0.048). Patients with both Met/Met genotype in the COMT Val158Met polymorphism and Val/Val genotype in the BDNF Val66Met polymorphism suffered from more health problems than those carrying other variants (P = 0.030) and had lower motivation to change drinking patterns (P = 0.031). Conclusions: Patients carrying both the BDNF Val66Val and COMT Met158Met variants had higher alcohol consumption. These effects may be influenced by the effects of BDNF and COMT on dopamine responses to alcohol. Motivation-enhancing strategies might benefit the group of patients identified by genotyping in this study, and also treatment aimed at reducing alcohol consumption.

The association between impulsivity, emotion regulation, and symptoms of alcohol use disorder

Emotion dysregulation and impulsivity are important factors influencing the development and course of alcohol dependence. However, few empirical studies investigate the association between different aspects of impulsivity (cognitive, attentional, behavioral), emotion regulation, and alcohol use disorder symptoms in the same model. The goal of this study was to assess the association between emotion regulation and different facets of impulsivity among patients with an alcohol use disorder and healthy controls. The sample was comprised of 273 individuals: 180 participants with an alcohol use disorder undergoing inpatient alcohol treatment and 93 healthy controls. Emotion regulation was assessed using the Schutte Self-Report Emotional Intelligence Test subscale. Impulsivity was assessed with Barratts Impulsiveness Scale (BIS-11). Statistical models tested both the BIS-11 total score, as well as three secondary factors (non-planning, attentional, and motor impulsivity). Findings indicate that individuals with alcohol use disorder symptoms were characterized by poor emotion regulation and high levels of impulsivity in all analyzed domains. Moreover, path analytic models indicated that after accounting for demographic factors (i.e., biological sex, age, education) there was evidence for a significant indirect effect of alcohol use disorder symptomatology on non-planning and attentional impulsivity via emotion regulation. There was no association between emotion regulation and motor impulsivity. These findings indicate the importance of targeting emotion regulation skills as well as behavioral control when treating patients with alcohol use disorder.