Association of rs11081062 polymorphism of DLGAP1 gene and levels of SLC1A1 protein with obsessive-compulsive disorder.

Glutamate is an important neurotransmitter known to be effective in obsessive-compulsive disorder (OCD). The aim of this study is to investigate the relationship between the DLGAP1 gene encoding the scaffold protein of ionotropic glutamate receptors and the SLC1A1 gene encoding the glutamate transporter protein with OCD. Study groups consisted of 95 patients with OCD and 100 healthy controls. The severity of OCD in the patient group was determined by using the Y-BOCS. Single nucleotide polymorphisms of rs11081062 (C/T) in DLGAP1 and rs587777696 (C/T) in SLC1A1 were analyzed by real-time PCR. Levels of SLC1A1 protein were determined by ELISA. A significant difference was found between genotype distributions of rs11081062 in DLGAP1 in study groups (p < 0.001). No significant association was found rs587777696 in SLC1A1 in OCD patients and controls. SLC1A1 protein levels were found to be lower in OCD patients compared to controls (p = 0.005). According to OCD risk estimates for genotypes distributions of rs11081062 in DLGAP1, having CT + TT genotypes was associated with the occurrence of sexual and religious obsessions and counting compulsions (p = 0.038, OR = 2.98; p = 0.033, OR = 3.43; p = 0.035, OR = 2.66, respectively). CT genotype in DLGAP1 rs11081062 polymorphism was found to increase the risk of OCD in the female gender (p = 0.042, OR = 3.01). This study suggests that rs11081062 in DLGAP1 may be associated with OCD and that SLC1A1 protein levels may be involved in the occurrence of OCD. We believe that our research can contribute to the understanding of the importance of glutamate in OCD.

The effects of 5-HTTLPR/rs25531 serotonin transporter gene polymorphisms on antisocial personality disorder among criminals in a sample of the Turkish population.

Antisocial personality disorder (ASPD) is a cluster B personality disorder characterized by a disposition for criminal behaviors. It has been determined by previous studies that ASPD may have a genetic origin and the human serotonin transporter gene (SLC6A4) is one of the two serotonergic genes expected to be associated with this disorder. 5-HTT-linked polymorphic promoter region (5-HTTLPR) is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter. Among many polymorphisms in SLC6A4, 5-HTTLPR an insertion/deletion (indel) polymorphism and rs25531 single nucleotide polymorphism (SNP) in the 5-HTTLPR polymorphic region contribute to the regulation of SLC6A4 expression. In this study, we aimed to reveal the relationship between frequencies of 5-HTTLPR variants and ASPD among criminals in the Turkish population. Moreover, it was also attempted to figure out the SLC6A4 gene expression level differences regarding these polymorphisms. The 5-HTTLPR/rs25531 genotypes were determined by PCR and restriction length polymorphism (RFLP) analyses and quantitative real-time-PCR was done for measuring the gene expression levels in the case and control groups. Although no significant difference was observed in the distributions of the 5-HTTLPR/rs25531 polymorphisms between the case and control groups, SLC6A4 expression level in the control group was found significantly higher than the case group (p < 0.0001). There was also no significant difference between genotypes in terms of mRNA expression levels in either the control or the case group. According to our results, ASPD in Turkish society is associated with the SLC6A4 gene expression levels, though the distributions of 5-HTTLPR polymorphisms are not different. This study sheds light on future relevant studies as the first study which is conducted in criminals with ASPD in the Turkish community.

Catechol-O-Methyltransferase Val158Met and brain-derived neurotrophic factor Val66Met gene polymorphisms in paraphilic sexual offenders.

BACKGROUND: Child sexual abuse (CSA) is an important problem worldwide. The reason of sex abuse is considered as multifactorial. Genetic contribution reported by recent studies is a significant evidence for this pathologic behavior. Catechol-O-Methyltransferase (COMT) is an enzyme in the metabolic inactivation of catecholamine and substances containing catecholamines such as dopamine, epinephrine, and norepinephrine. COMT polymorphism causes functional changes in COMT enzyme activity. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor usually synthesized from central nervous system neurons. With the effect of BDNF, dopamine and serotonin play important roles on neurogenesis, survival, and synaptic plasticity. AIM: This study aims to examine COMT Val158Met (rs4680) and BDNF Val66Met (rs6265) polymorphisms in CSA. SETTINGS AND DESIGN: This was a case-control study. MATERIALS AND METHODS: Seventy paraphilic child sexual abuser patients and seventy age- and gender-matched healthy controls participated in this study. COMT Val158Met and BDNF Val66Met polymorphisms were genotyped by real-time polymerase chain reaction assay. RESULTS: COMT Val158Met genotype frequencies were determined as GG 31.4%, GA 45.7%, and AA 22.9% in patients; GG 24.3%, GA 45.7%, and AA 8.6% in controls; and exhibited a positive relationship between the groups (P = 0.018). BDNF Val66Met genotype frequencies were determined as GG 77.1%, GA 21.4%, and AA 1.4% in patients; GG 65.7%, GA 31.4%, AA 2.9% in controls; and no significant relationship was observed between the groups (P = 0.317). CONCLUSIONS: This research investigated COMT (Val158Met) and BDNF (Val66Met) in paraphilic child sexual offenders. A positive relationship was found for COMT gene; however, no significant relation was observed for BDNF gene between paraphilic sexual offenders and controls.

Orexin/hypocretin receptor, Orx1, gene variants are associated with major depressive disorder.

Objective: Orexins (hypocretins) are neuropeptides expressed in hypothalamic neurons and have regulatory roles in feeding/drinking behaviours, endocrine functions and sleep/wakefulness state. Major depressive disorder (MDD) is a major mood disorder and neurotransmitter dysfunction in hypothalamic neurons may have roles in its formation. Hence, we conducted experiments to determine whether orexin receptor 1 and 2 (Orx1, Orx2) genes were associated with MDD development. Methods: Seventy-five MDD patients and 87 healthy controls were enrolled for the study. Genotyping was carried out with real-time polymerase chain reaction (RT-PCR). Hamilton Rating-Scale for Depression (HRSD) and Beck Depression Inventory (BDI) were utilized to evaluate depressive symptom severity. Results: A significant relation was found in genotype frequencies of Orx1 rs10914456 and rs2271933 variants between MDD patients and controls (p = .009, p = .006). Rs10914456 CC genotype increased MDD risk 3.57 times more than carrying other genotypes (p = .008, OR =3.57;95% CI: 1.39-9.14). However, no association was observed in Orx2 rs2653349 genotypes for MDD development (p > .05). Although statistically not significant, HRSD scores were diminished in MDD subjects carrying rs10914456 CC variants when compared with CT and TT variants (p = .069). Conclusion. This study suggests that, Orx1 rs10914456 and rs2271933 can be associated with MDD development. Hence, Orx1 rs10914456 variants may affect depressive symptom severity.

Genetic Polymorphism of the Serotonin Transporter Gene, SLC6A4 rs16965628, Is Associated with Obsessive Compulsive Disorder.

Obsessive compulsive disorder (OCD) is a psychiatric disorder characterized by obsessive ideas and compulsive behaviors. Genetic studies have centered on candidate genes involved in OCD etiology related to serotonergic and dopaminergic systems. In this study, the relationship between cathechol-O-methyltransferase (COMT) -287A/G (rs2097063), serotonin transporters 5-HTTLPR I/D, and SLC6A4 rs16965628 polymorphisms in 80 OCD patients and 100 healthy controls was determined. Patients and controls were genotyped for COMT rs2097063 and SLC6A4 rs16965628 polymorphisms by real-time polymerase chain reaction (PCR). The 5-HTTLPR I/D polymorphism was genotyped using PCR and agarose gel electrophoresis. Severity of symptoms was checked with a Yale-Brown Obsession Compulsion Scale (Y-BOCS). When the OCD group and controls were compared, no significant difference was found between COMT -287A/G (rs2097063), 5-HTTLPR I/D polymorphisms, and OCD. However, a significant difference was found between 5-HTT rs16965628 polymorphism and OCD (p=0.025, OR=3.43, 95% CI 1.41-10.35). In addition, the G allele frequency was found to be higher for rs16965628 in the OCD group. No significant difference was observed between COMT -287A/G (rs2097063), SLC6A4 rs16965628, and 5-HTTLPR I/D polymorphisms and Y-BOCS scores (p>0.05). There was also lack of correlation between Yale-Brown scores and gender of OCD patients. On the other hand, combined genotypes of SLC6A4 rs16965628 GG+GC were found to be risk factors for OCD development (p=0.02, OR=3.464; 95% CI 1.214-9.883) in logistic regression analysis adjusted for age and gender. Our findings suggest that subjects carrying the G allele of rs16965628 have genetic susceptibility to OCD. These data are the first to suggest that polymorphism in serotonin transporter (rs16965628) is associated with the development of OCD in the Turkish population.

Pro198Leu polymorphism in the oxidative stress gene, glutathione peroxidase-1, is associated with a gender-specific risk for panic disorder.

OBJECTIVE: Panic disorder (PD) is an anxiety disorder characterized by sudden attacks of intense fear. Biochemical studies suggest that oxidative stress (OS) index is significantly higher in PD, and OS genes may participate in development of anxiety-like behavioral phenotypes. We aimed to investigate role of polymorphisms in OS gene, glutathione peroxidase-1 (GPX1), and DNA repair enzyme gene, 8-oxoguanine glycosylase-1 (OGG1), in PD patients. METHODS: GPX1 Pro198Leu (rs1050450) and OGG1 Ser326Cys (rs1052133) polymorphisms of 127 patients with PD and 151 disease-free controls were analyzed with real-time polymerase chain reaction. Severity of PD symptoms was assessed by Panic and Agoraphobia Scale (PAS). RESULTS: No significant relationship was found in genotype distributions of OGG1 Ser326Cys and GPX1 Pro198Leu polymorphisms between PD and control groups (p > 0.05). There was no significant relationship between OGG1 or GPX1 polymorphisms, and age of onset, agoraphobia, or PAS scores in PD group (p > 0.05). However, in GPX1 Pro198Leu polymorphism, C allele (Pro) was found to be more frequent in female subgroup of PD patients compared with that in males (p = 0.027). CONCLUSIONS: GPX1 Pro198Leu and OGG1 Ser326Cys polymorphisms were not associated with PD risk in Turkish patients. However, a gender-specific effect of GPX1 Pro198Leu C allele may be associated with PD development.

Genetic polymorphism of angiotensin I-converting enzyme (ACE), but not angiotensin II type I receptor (ATr1), has a gender-specific role in panic disorder.

AIMS: Angiotensins were shown to have some role in the development of panic disorder (PD). In this study, we aimed to determine the frequency of polymorphisms in two angiotensin-related genes, angiotensin I-converting enzyme (ACE) and angiotensin II type I receptor (ATr1), in a sample of Turkish patients with PD and to evaluate their association with PD development. METHODS: Polymerase chain reaction and restriction fragment length polymorphism was used to analyze ATr1 A1166C polymorphism, and only polymerase chain reaction was used to analyze functional ACE insertion/deletion polymorphism in 123 patients with PD and in 169 similarly aged disease-free controls. RESULTS: There was no significant difference in the genotype distribution between PD patients and controls for each polymorphism (P>0.05). Allele frequency of ACE insertion/deletion was borderline statistically significant between the groups (P=0.055; odds ratio: 1.39; 95% confidence interval: 0.99-1.95), and allele frequency of ATr1 A1166C was not significantly different between the groups (P=0.32; odds ratio: 0.81; 95% confidence interval: 0.53-1.22). CONCLUSION: This study suggests that polymorphisms of ACE I/D and ATr1 A1166C are not associated with risk of PD in Turkish patients. However, in ACE insertion/deletion polymorphism, the insertion allele was found to be more frequent in the male subgroup of patients (χ²=4.61, P=0.032) than in controls, suggesting a potential male-specific role of the less active ACE insertion allele in the pathogenesis of PD.

Assessment of quality of life and depression in spouses of patients with ankylosing spondylitis.

The objective of this study is to investigate the quality of life and the rates of depression in spouses/partners of patients with AS compared with spouses/partners of healthy controls". Twenty-five persons with AS and their 25 spouses (21 women and 4 men) and 25 healthy controls were recruited consecutively. All the subjects completed 36-item Short Form Health Survey (SF-36) questionnaire forms and 17-item Hamilton Depression Rating Scale (HAM-D17). Mean age was 35 ± 6.47 years in spouse group (SG) and 36.26 ± 5.93 in control group (CG). In SG and CG, the SF-36 subscale scores were compared using Mann-Whitney U test. Social functioning, mental health, emotional role, and general health were significantly (P < 0.05) lower in SG compared with CG. The average score of social functioning was found to be 65.41 in spouses of patients compared with healthy controls (90.75). Depression scores were significantly (P < 0.001) higher in SG compared with CG. Among SF-36 subgroups in spouses, general health perception had a negatively significant correlation with depression scores (P < 0.05) and duration of ankylosing spondylitis (P < 0.05). A positively significant correlation has been identified between bodily pain and depression scores in spouses (P < 0.05). Therefore, female partners of male patients were found to be more depressive. Being a spouse of a patient with AS significantly interferes with quality of life and increases the depression frequency.

Serotonin-2A receptor and catechol-O-methyltransferase polymorphisms in panic disorder.

Catechol-O-methyltransferase (COMT) and serotonin receptor 2A (5HTR2A) polymorphisms have been investigated for their possible role in panic disorder (PD). The aim of this study was to investigate the genotype distribution of the COMT val158met and 5HTR2A 102T/C polymorphisms in PD. COMT val158met is a polymorphism at codon 158 that results in variations in COMT enzymatic activity with high- (H) and low-activity (L) alleles. The 5HTR2A 102T/C polymorphism comprises a T-to-C mutation at position 102. The effects of symptom severity, gender, and age of onset were also investigated. The participants were 105 outpatients with PD and 130 controls. The severity of the symptoms of PD was assessed by the Panic and Agoraphobia Scale (PAS). Polymorphisms of the 5HTR2A and COMT genes were identified using polymerase chain reaction and restriction fragment length polymorphism analysis. A significant relationship was found between the COMT Val158Met polymorphism and PD. No significant differences were found in genotype distributions or allele frequencies of the 5HTR2A polymorphisms between the PD and control groups. There were no significant relationships between the COMT and 5HTR2A polymorphisms and age of onset, gender, presence of agoraphobia, or PAS scores in the PD group (p>0.05).

Management of marked liver enzyme increase during clozapine treatment: a case report and review of the literature.

OBJECTIVE: Clozapine-induced hepatotoxicity is not infrequent and usually transient. It mostly causes asymptomatic elevation of liver transaminases. "Elevation in liver enzymes to what extent should preclude further treatment?" or "Is only a dose-reduction sufficient?" are questions yet to be answered. The present article uses a case report to discuss the treatment alternatives when liver enzymes reach three times the upper normal limits during the clozapine therapy. METHODS: In the following case report, the authors describe a 27-year-old male patient diagnosed with schizophrenia, resistant to different atypical and typical antipsychotics. Based on the pathological findings of our patient and a review of the literature, the author summarizes the reasons for the liver enzymes increase and treatment alternatives during clozapine treatment. RESULTS: Substantial improvement was achieved with clozapine therapy. Increase in liver enzymes at the beginning of the clozapine treatment was successfully managed with a multidisciplinary approach: the treatment was initially withdrawn, afterwards restarted, and carefully continued. CONCLUSION: The authors demonstrate that clozapine may be cautiously continued in selected patients who showed marked psychiatric improvement with clozapine in the face of liver enzyme elevation.

A prospective randomized single-blind, multicenter trial comparing the efficacy and safety of paroxetine with and without quetiapine therapy in depression associated with anxiety.

OBJECTIVE To evaluate quetiapine as an adjunct to paroxetine in patients with comorbid depression and anxiety. METHOD Prospective, multicenter, single-blind trial of patients with DSM-IV major depression and associated anxiety, who were randomized to an 8-week treatment with paroxetine alone (n=54) or paroxetine+quetiapine (n=58). Quetiapine was dosed to 200 mg/day and paroxetine to 60 mg/day, as required. RESULTS Decrease in HAM-A scores was significantly greater in the combined therapy group than with paroxetine alone at weeks 2, 4, 6 and LOCF (P<0.008). Decrease in HAM-D scores was significantly greater in the combined therapy group than with paroxetine alone throughout the study period (P<0.008). Regarding adverse events, it was found that increases in anxiety and insomnia were more prevalent in the paroxetine only group, while increased appetite was more prevalent when quetiapine was added (P<0.05). CONCLUSION Quetiapine added to paroxetine is well tolerated and may speed up and improve response in patients with comorbid depression and anxiety.