Genetic association study reveals impact of interleukin 10 polymorphisms on cognitive functions in schizophrenia.

AIM: Cognitive deficits are the core factors impacting quality of life among patients diagnosed with schizophrenia. Effective method of treatment for this domain of symptoms remains lacking. Recent evidence suggests the link between impaired cognition and aberrant inflammatory response. Severity of symptoms might be linked to individual genetic predispositions and single-nucleotide polymorphisms (SNPs) in genes encoding interleukins and their receptors. Current genetic association studies include anti-inflammatory interleukins, such as IL10. Functional polymorphisms of IL10 (rs1800871, rs18008729) have been indicated to affect information processing in schizophrenia. MATERIALS AND METHODS: In this study, we analyzed the potential impact of 27 functional SNPs in 8 cytokine genes on cognitive parameters measured by Wisconsin card-sorting test (WCST) in schizophrenia group (n = 150) and healthy controls (n = 152). RESULTS: We found significant associations of two functional polymorphisms of IL10 (rs1800871, rs1800872) and WCST results. Allele A carriers in rs1800871 performed significantly better in Percent of Conceptual Level Responses (CLR%). Allele A carriers in rs1800871 and allele T carriers in rs1800872 obtained better results in Completed Categories (CC). The impact of illness duration was observed, with better performance of recent-onset patients. CONCLUSIONS: Results of this study indicate that genetic variants of inflammatory response are associated with cognitive deficits in schizophrenia. The role of cytokines in schizophrenia need to be investigated in the aspect of pro-/anti-inflammatory imbalance. Altered inflammatory response promote chronic mild inflammation in the brain and aberrant synaptic plasticity.

Elevated Epidermal Growth Factor (EGF) as Candidate Biomarker of Mood Disorders-Longitudinal Study in Adolescent and Young Adult Patients.

Bipolar disorder (BD) is a chronic mental disorder that affects more than 1% of the population worldwide. Over 65% of patients experience early onset of the disease. Most cases of juvenile bipolar disorder begin with a depressed mood episode, and up to 50% of youth initially diagnosed with major depression go onto developing a BD. Our study aimed to find biomarkers of diagnosis conversion in young patients with mood disorders. We performed a two-year follow-up study on 79 adolescent patients diagnosed with MDD or BD, with a detailed clinical assessment at five visits. We monitored diagnosis change from MDD to BD. The control group consisted of 31 healthy youths. According to the neurodevelopmental and neuroimmunological hypotheses of mood disorders, we analyzed serum levels of brain-derived neurotrophic factor (BDNF), proBDNF, epidermal growth factor (EGF), migration inhibitory factor (MIF), stem cell factor (SCF), and correlations with clinical factors. We detected a significant disease-dependent increase in EGF level in MDD and BP patients at baseline exacerbation of depressive or hypomanic/manic episodes as well as in euthymic state compared to healthy controls. No potential biological predictors of disease conversion were found. Replication studies on a larger cohort of patients are needed.

Impulsivity as a Risk Factor for Suicide in Bipolar Disorder.

The accurate assessment of suicide risk in psychiatric, especially affective disorder diagnosed patients, remains a crucial clinical need. In this study, we applied temperament and character inventory (TCI), Barratt impulsiveness scale 11 (BIS-11), PEBL simple reaction time (SRT) test, continuous performance task (CPT), and Iowa gambling task (IGT) to seek for variables linked with attempted suicide in bipolar affective disorder group (n = 60; attempters n = 17). The main findings were: strong correlations between self-report tool scores and objective parameters in CPT; the difference between attempters and non-attempters was found in the number of correctly responded trials in IGT; only one parameter differed between attempters and non-attempters in BPI diagnosis; and no significant differences between suicide attempters and non-attempters in TCI, BIS-11, and SRT were found. These justify the conclusion that impulsivity itself is not a strong predictor, and used as a single variable might not be sufficient to indicate the high suicide risk group among bipolar patients.

Longitudinal assessment of S100B serum levels and clinical factors in youth patients with mood disorders.

Mood disorders have been discussed as being in relation to glial pathology. S100B is a calcium-binding protein, and a marker of glial dysfunctions. Although alterations in the S100B expression may play a role in various central nervous system diseases, there are no studies on the potential role of S100B in mood disorders in adolescents and young adults . In a prospective two-year follow-up study, peripheral levels of S100B were investigated in 79 adolescent/young adult patients (aged 14-24 years), diagnosed with mood disorders and compared with 31 healthy control subjects. A comprehensive clinical interview was conducted which focused on clinical symptoms and diagnosis change. The diagnosis was established and verified at each control visit. Serum S100B concentrations were determined. We detected: lower S100B levels in medicated patients, compared with those who were drug-free, and healthy controls; higher S100B levels in a depressed group with a family history of affective disorder; correlations between age and medication status; sex-dependent differences in S100B levels; and lack a of correlation between the severity of depressive or hypo/manic symptoms. The results of our study indicate that S100B might be a trait-dependent rather than a state-dependent marker. Due to the lack of such studies in the youth population, further research should be performed. A relatively small sample size, a lack of exact age-matched control group, a high drop-out rate.

Transcriptome Changes in Three Brain Regions during Chronic Lithium Administration in the Rat Models of Mania and Depression.

Lithium has been the most important mood stabilizer used for the treatment of bipolar disorder and prophylaxis of manic and depressive episodes. Despite long use in clinical practice, the exact molecular mechanisms of lithium are still not well identified. Previous experimental studies produced inconsistent results due to different duration of lithium treatment and using animals without manic-like or depressive-like symptoms. Therefore, we aimed to analyze the gene expression profile in three brain regions (amygdala, frontal cortex and hippocampus) in the rat model of mania and depression during chronic lithium administration (2 and 4 weeks). Behavioral changes were verified by the forced swim test, open field test and elevated maze test. After the experiment, nucleic acid was extracted from the frontal cortex, hippocampus and amygdala. Gene expression profile was done using SurePrint G3 Rat Gene Expression whole transcriptome microarrays. Data were analyzed using Gene Spring 14.9 software. We found that chronic lithium treatment significantly influenced gene expression profile in both mania and depression models. In manic rats, chronic lithium treatment significantly influenced the expression of the genes enriched in olfactory and taste transduction pathway and long non-coding RNAs in all three brain regions. We report here for the first time that genes regulating olfactory and taste receptor pathways and long non-coding RNAs may be targeted by chronic lithium treatment in the animal model of mania.

Genes involved in glucocorticoid receptor signalling affect susceptibility to mood disorders.

OBJECTIVES: In mood disorders chronic stress contributes to decreased glucocorticoid receptor signalling in the brain and resistance in the periphery. We hypothesised that aberrant glucocorticoid receptor function may result from genetic predisposition and that decreased GR signalling in the brain correlates with the expression of genes regulating GR complex formation. METHODS: We performed the association analysis of 698 patients: 490 patients with bipolar disorder and 208 patients with major depressive disorder and 564 control subjects. We genotyped 11 variants using TaqMan assays. Gene expression in the brain tissue was done in male Wistar rats after chronic mild stress protocol. The SRSF5 serum concentration was performed using ELISA. Data were analysed in Statistica and GraphPad. RESULTS: We found an association of STIP1 and SRSF5 variants with major depressive disorder and BAG1 variant with bipolar disorder. Gene expression analysis in a rat model of depression confirmed significant changes in the expression of SRSF5, BAG1, and FKBP4 in the brain. For SRSF5, we observed significantly increased expression in the serum of depressed females and male rats exposed to chronic stress. CONCLUSIONS: Our results indicate the involvement of genes associated with GR function, SRSF5, BAG1, and FKBP4 with susceptibility to mood disorders.

Correlation of metabolic parameters, neurotrophin-3, and neurotrophin-4 serum levels in women with schizophrenia and first-onset depression.

BACKGROUND: Neurotrophin-3 (NTF3) and neurotrophin-4 (NTF4) play a crucial role in the neurodevelopment, differentiation, survival, and protection of neurons in different brain regions. Schizophrenia and depression are highly associated with metabolic abnormalities. Longitudinal and cross-sectional comparisons of NTF3 and NTF4 levels, as well as clinical and metabolic parameters, were studied in schizophrenia, first-episode depression, and control groups. MATERIALS AND METHODS: Serum NTF3 and NTF4 levels, body mass index (BMI), fasting serum glucose and lipid profile: cholesterol, triglyceride, high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) were measured at baseline and week 8 in 133 women: 55 patients with schizophrenia (19 with first-episode and 36 chronic), 30 patients with a first-episode depression and 48 healthy controls. The severity of the symptoms was evaluated with the Positive and Negative Syndrome Scale, 17-item Hamilton Depression Rating Scale and the Beck Depression Inventory. RESULTS: Longitudinal and cross-sectional comparisons did not detect any differences in the serum levels of NTF3 and NTF4 between studied groups. NTF3 and NTF4 levels were strongly correlated. Correlation of NTF3 and HDL-C levels at baseline was observed. Significant changes in cholesterol and fasting serum glucose levels in first-episode depression patients during 8 weeks of treatment were detected. Significant differences in BMI and LDL-C levels between schizophrenia and first-episode depression patients were discovered. CONCLUSIONS: To our knowledge, this is the first research which correlates NTF3 and NTF4 with metabolic parameters. Our study does not support the theory that the peripheral levels of NTF3 and NTF4 are disturbed in schizophrenia or first-episode depression.

Elevated brain-derived neurotrophic factor (BDNF) serum levels in an acute episode of schizophrenia in polish women: Correlation with clinical and metabolic parameters.

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of psychiatric disorders. Schizophrenia is associated with metabolic abnormalities and BDNF regulates energy homeostasis and glucose metabolism in peripheral tissues. The aim of this study was to examine serum levels of BDNF in schizophrenic women during 8 weeks of treatment and control group, and its correlation with clinical and metabolic parameters. The study was performed on a group of 96 women: 55 diagnosed with paranoid schizophrenia according to DSM-IV criteria, and 41 healthy controls. Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of schizophrenia. BDNF serum levels and metabolic parameters: fasting serum glucose, total cholesterol, triglyceride (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C) were measured at baseline and week 8 of treatment. BDNF serum levels were significantly elevated in medicated patients with schizophrenia comparing to controls. After 8 weeks of antipsychotic treatment, BDNF levels did not significantly change. Increase in TG and TG/HDL-C ratio and a decrease in HDL-C was detected in medicated patients. Correlation between BDNF and lipid profile as well as symptoms severity was found. In our study we detected abnormalities in BDNF levels and lipid profile in medicated schizophrenic women in Polish population.

Clock genes polymorphisms in male bipolar patients with comorbid alcohol abuse.

BACKGROUND: Psychiatric comorbidity affects 24-65% patients with bipolar disorder (BD), 45% of which have alcohol abuse/dependence (AAD). Despite the fact that BD has an equal incidence in both genders, AAD more often occurs in men. We hypothesized that the presence of BD and AAD, reported as a secondary diagnosis, may result from a common genetic background. However, specific genetic factors predispose to gender differences. METHODS: Based on the relationship between circadian clock genes pathway and BD/AAD we decided to test the connection of four core clock genes with common genetic background of both diseases. We analyzed 436 patients with BD, among which 17% were diagnosed with AAD. The control group consisted of 417 healthy subjects. We analyzed 44 SNPs of the previously described core molecular clock genes: CLOCK, ARNTL, TIMELESS and PER3. RESULT: We found association of ARNTL gene (rs11600996) and PER3 gene (rs228642) polymorphisms with an increased risk of BD/AAD in a group of male patients. We also found that two other polymorphisms of PER3 gene, rs228682 and rs2640909, were associated with both AAD and family history of affective disorders. LIMITATIONS: Possible factors that could have influenced the results are: relatively small sample size, gender disproportion and unverifiable data form the patient interview. CONCLUSIONS: Our study confirms the existence of a link between clock genes and increased risk of alcohol abuse/dependence in male patients and the accumulation of risk genes in patients with a positive family history.

Genes involved in stress response influence lithium efficacy in bipolar patients.

OBJECTIVES: In mood disorders, chronic stimulation with stress results in aberrant regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Lithium was shown to influence HPA axis function. The underlying genetic background as well as environmental context may influence the stress response, and therefore lithium efficacy. The aim of the present study was to analyze if genetic variants located in genes involved in HPA axis regulation affect the response to long-term lithium treatment in bipolar patients. METHODS: We included 93 patients with bipolar disorder (32 males and 61 females), aged 31-80 years. The patients had been treated with lithium carbonate for at least 5 years. The magnitude of the lithium response was assessed using the Alda scale. Genotyping was performed for 28 polymorphisms in the genes encoding the following proteins involved in HPA axis regulation: corticotropin-releasing hormone receptor 1 (CRHR1), arginine vasopressin receptor 1B (AVPR1b), FK506 binding protein (FKBP) 5, FKBP4, BCL2-associated athanogene 1 (BAG1), stress induced phosphoprotein 1 (STIP1), glucocorticoid-induced transcript 1 (GLCC1), dual specificity phosphatase 1 (DUSP1) serine and arginine rich splicing factor (SRSF) 3, SRSF9, SRSF5, and acid phosphatase 1 (ACP1). Linkage disequilibrium and haplotype analysis were then performed, followed by statistical analysis (Statistica v.12; Stasoft, Krakow, Poland). RESULTS: We found a correlation between stressful life events at first episode and worse response to lithium (P=.019). In single marker analysis, we observed a significant association between three FKBP5 polymorphisms (rs1360780, rs7748266 and rs9296158), one ACP1 variant (rs300774) and one glucocorticoid-induced transcript 1 gene (GLCC1) variant (rs37972) and the degree of lithium response. Five out of seven FKBP5 polymorphisms showed strong linkage with one haplotype demonstrating an association with lithium efficacy (P=.008). No relationship was found between the other analyzed polymorphisms and lithium response. CONCLUSION: The response to lithium may depend on the variants of genes regulating the HPA axis and stressful life events in bipolar patients.

Val66Met functional polymorphism and serum protein level of brain-derived neurotrophic factor (BDNF) in acute episode of schizophrenia and depression.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) influences neuron differentiation during development as well as the synaptic plasticity and neuron survival in adulthood. BDNF has been implicated in the pathogenesis of schizophrenia and depression. Val66Met polymorphism and BDNF serum level are potential biomarkers in neuropsychiatric disorders. The aim of this study was to determine the effect of BDNF gene Val66Met functional polymorphism on serum BDNF concentration in patients with schizophrenia, during depression episode and in healthy control group. METHODS: 183 participants were recruited (61 patients with depressive episode, 56 females with schizophrenia, 66 healthy controls) from Polish population. Serum BDNF levels were measured using ELISA method. Val66Met polymorphism was genotyped using PCR- RFLP method. RESULTS: Serum BDNF levels were not associated with Val66Met polymorphism in either of the groups. A significant increase of BDNF level in schizophrenia (p = 0.0005) and depression (p = 0.026) comparing to the control group has been observed. CONCLUSIONS: Our results suggest that the functional Val66Met BDNF polymorphism is not associated with BDNF serum levels, which is in line with previous findings. Replication studies on larger groups are needed.

Brain-derived neurotrophic factor (BDNF) serum level in women with first-episode depression, correlation with clinical and metabolic parameters.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) influences neuron differentiation during development, as well as the synaptic plasticity and neuron survival in adulthood. BDNF has been implicated in the pathogenesis of psychiatric disorders and its serum level is a potential biomarker for depression. The aim of this study was to examine serum levels of BDNF in first-episode depression and its correlation with clinical and metabolic parameters. MATERIALS AND METHODS: The study was performed on a group of 60 women: 30 diagnosed with a first-episode of depression and 30 healthy controls. 17-Item Hamilton Depression Rating Scale (HDRS-17) was used to assess the severity of depression. Patients were randomly chosen for treatment with sertraline or venlafaxine. BDNF serum levels and metabolic parameters: fasting serum glucose, cholesterol, triglyceride (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C) were measured at baseline and week 8 of treatment. RESULTS: There were no differences between BDNF level in depressed patients compared with the healthy controls. Lack of differences in medication effect of sertraline or venlafaxine on HDRS-17 scores during 8 weeks of treatment was observed. Correlation of BDNF at baseline and fasting serum glucose at baseline and week 8 was detected. CONCLUSIONS: Correlations of BDNF serum levels with metabolic parameters were observed.

Glial Cell Line-Derived Neurotrophic Factor (GDNF) serum level in women with schizophrenia and depression, correlation with clinical and metabolic parameters.

AIM: Neurotrophic factors have been implicated in neuropsychiatric disorders, including schizophrenia and depression. Glial Cell Line-Derived Neurotrophic Factor (GDNF) promotes development, differentiation, and protection of dopaminergic, serotonergic, GABAergic and noradrenergic neurons as well as glial cells in different brain regions. This study examined serum levels of GDNF in schizophrenia and depression and its correlation with metabolic parameters during 8 weeks of treatment. METHODS: Serum GDNF level, fasting serum glucose and lipid profile were measured at baseline and week 8 in 133 women: 55 with schizophrenia, 30 with a first episode depression and 48 healthy controls. The severity of the symptoms was evaluated using Positive and Negative Syndrome Scale (PANSS), 17-item Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). RESULTS: There was statistically significant higher GDNF level in schizophrenia at baseline when compared with week 8. Correlations of GDNF with PANSS in schizophrenia and cholesterol level in depression have also been detected. CONCLUSIONS: To our knowledge, this is the first study which correlates GDNF levels with metabolic parameters. Our results show no differences in GDNF serum level between schizophrenia, a first depressive episode, and healthy controls. GDNF serum level did not correlate with metabolic parameters except for total cholesterol in depression.

Venlafaxine and sertraline does not affect the expression of genes regulating stress response in female MDD patients. / Wenlafaksyna i sertralina nie wplywaja na ekspresje genów regulujacych poziom kortyzolu u kobiet chorych na depresje.

OBJECTIVES: The aim of this study was to analyze the expression of 3 genes involved in the regulation of HPA axis: GR, HSP90 and FKBP5, in patients with major depressive disorder (MDD) before antidepressant treatment and after 8 weeks of pharmacotherapy. Additionally, we analyzed the level of glucocorticoid receptor isoforms before and after treatment. METHODS: The study included 30 female patients (aged 18-60 years), with major depres- sive disorder diagnosed on the basis of the Structured Clinical Interview for DSM-IV (SCID). Antidepressant treatment included use of sertraline or venlafaxine. The assessment of patients' mental state (severity of depression) was checked by the Hamilton Depression Rating Scale (HDRS). After 8 weeks of treatment, the same clinical and molecular tests were performed. All of the patients underwent dexamethasone suppression test (DST). MRNA was isolated from the peripheral blood to evaluate the expression of the studied genes using real-time PCR with TaqMan probes. The concentration of GR isoforms (α and ß) in serum was also determined using ELISA. Statistical analysis was performed using Statistica v.12.0 software. RESULTS: The abnormal cortisol level was only seen in 20% of patients. Dysregulation on HPA axis was observed in 10% of patients. We observed significant clinical improvement after 8 weeks of pharmacotherapy in all patients. Almost the whole group of patients (except one patient) showed full remission of symptoms. We observed significant moderate correlation between cortisol level after DST before treatment and after 8 weeks of pharmacotherapy (r2 = 0.44). The results showed no significant difference in the expression of 3 analyzed genes compared before and after 8 weeks of therapy. The results of ELISA showed decreased level of α isoform after pharmacotherapy, independent of drug. CONCLUSIONS: The results showed no significant changes in the expression of genes involved in the stress axis activity during antidepressant therapy.

Family-based association study of interleukin 10 (IL10) and interleukin 10 receptor alpha (IL10RA) functional polymorphisms in schizophrenia in Polish population.

Schizophrenia is a heterogeneous disorder and its etiology remains incompletely elucidated. Among possible causes, immunological factors have been implicated in its pathogenesis and course. Interleukin-10 (IL10) and it's receptor IL10RA may play an important role for immunological aspects in etiologies of major psychiatric disorders including schizophrenia. The aim of this study was to perform a transmission disequilibrium test (TDT) on a group of 146 schizophrenia trios from the Polish population. Functional polymorphisms from IL10 (rs1800872, rs1800871, rs1800896, rs1800890, and rs6676671) and IL10RA (rs3135932 and rs2229113) genes were analyzed. A lack of association with schizophrenia was detected for IL10 and IL10RA single polymorphisms and haplotypes.

Association of the glucocorticoid receptor gene polymorphisms and their interaction with stressful life events in Polish adolescent girls with anorexia nervosa.

BACKGROUND: Disturbances in stress response mechanisms and hypothalamic-pituitary-adrenal axis (HPA) functioning are considered important factors involved in the pathophysiology of anorexia nervosa (AN). Thus, genetic variations in the end effector of HPA - glucocorticoid receptor gene and relationships to stressful life events (SLE) may be connected to a higher risk of illness. The aim of the study was examining the association between glucocorticoid receptor gene (NR3C1) polymorphisms and risk factors among stressful life events in AN patients. SUBJECTS AND METHODS: This study comprised 256 patients with AN and 167 control subjects. The questionnaires examining brief history of the mother's pregnancy and long-acting stress factors, as well as life events checklist to assess stressful life events during the 6 months prior to hospitalization were used. The eight common SNPs (rs6198, rs6191, rs6196, rs258813, rs33388, rs41423247, rs56149945 and rs10052957) of NR3C1 gene were genotyped. RESULTS: The association of five polymorphisms (rs6191, rs258813, rs33388, rs41423247 and rs10052957) and one complex allele (TCAGT) of NR3C1 gene with increased risk of AN were found. However, no significant correlations between early, long-acting and predicting hospitalization SLE and any of the analyzed polymorphisms were observed. CONCLUSIONS: The results confirm that the NR3C1 gene is associated with AN risk regardless of the type of stressful triggering factors.

An Association Between Functional Polymorphisms of the Interleukin 1 Gene Complex and Schizophrenia Using Transmission Disequilibrium Test.

IL1 gene complex has been implicated in the etiology of schizophrenia. To assess whether IL1 gene complex is associated with susceptibility to schizophrenia in Polish population we conducted family-based study. Functional polymorphisms from IL1A (rs1800587, rs17561, rs11677416), IL1B (rs1143634, rs1143643, rs16944, rs4848306, rs1143623, rs1143633, rs1143627) and IL1RN (rs419598, rs315952, rs9005, rs4251961) genes were genotyped in 143 trio with schizophrenia. Statistical analysis was performed using transmission disequilibrium test. We have found a trend toward an association of rs1143627, rs16944, rs1143623 in IL1B gene with the risk of schizophrenia. Our results show a protective effect of allele T of rs4251961 in IL1RN against schizophrenia. We also performed haplotype analysis of IL1 gene complex and found a trend toward an association with schizophrenia of GAGG haplotype (rs1143627, rs16944, rs1143623, rs4848306) in IL1B gene, haplotypes: TG (rs315952, rs9005) and TT (rs4251961, rs419598) in IL1RN. Haplotype CT (rs4251961, rs419598) in IL1RN was found to be associated with schizophrenia. After correction for multiple testing associations did not reach significance level. Our results might support theory that polymorphisms of interleukin 1 complex genes (rs1143627, rs16944, rs1143623, rs4848306 in IL1B gene and rs4251961, rs419598, rs315952, rs9005 in IL1RN gene) are involved in the pathogenesis of schizophrenia, however, none of the results reach significance level after correction for multiple testing.

Association study of functional polymorphisms in interleukins and interleukin receptors genes: IL1A, IL1B, IL1RN, IL6, IL6R, IL10, IL10RA and TGFB1 in schizophrenia in Polish population.

Schizophrenia has been associated with a large range of autoimmune diseases, with a history of any autoimmune disease being associated with a 45% increase in risk for the illness. The inflammatory system may trigger or modulate the course of schizophrenia through complex mechanisms influencing neurodevelopment, neuroplasticity and neurotransmission. In particular, increases or imbalance in cytokine before birth or during the early stages of life may affect neurodevelopment and produce vulnerability to the disease. A total of 27 polymorphisms of IL1N gene: rs1800587, rs17561; IL1B gene: rs1143634, rs1143643, rs16944, rs4848306, rs1143623, rs1143633, rs1143627; IL1RN gene: rs419598, rs315952, rs9005, rs4251961; IL6 gene: rs1800795, rs1800797; IL6R gene: rs4537545, rs4845617, rs2228145, IL10 gene: rs1800896, rs1800871, rs1800872, rs1800890, rs6676671; IL10RA gene: rs2229113, rs3135932; TGF1B gene: rs1800469, rs1800470; each selected on the basis of molecular evidence for functionality, were investigated in this study. Analysis was performed on a group of 621 patients with diagnosis of schizophrenia and 531 healthy controls in Polish population. An association of rs4848306 in IL1B gene, rs4251961 in IL1RN gene, rs2228145 and rs4537545 in IL6R with schizophrenia have been observed. rs6676671 in IL10 was associated with early age of onset. Strong linkage disequilibrium was observed between analyzed polymorphisms in each gene, except of IL10RA. We observed that haplotypes composed of rs4537545 and rs2228145 in IL6R gene were associated with schizophrenia. Analyses with family history of schizophrenia, other psychiatric disorders and alcohol abuse/dependence did not show any positive findings. Further studies on larger groups along with correlation with circulating protein levels are needed.

Family-based association study of interleukin 6 (IL6) and its receptor (IL6R) functional polymorphisms in schizophrenia in the Polish population.

Schizophrenia is a heterogeneous disorder and its etiology remains incompletely elucidated. Among possible causes, immunological factors have been implicated in its pathogenesis and course. The inflammatory system may trigger or modulate the course of schizophrenia through complex mechanisms influencing neurodevelopment, neuroplasticity and neurotransmission. Recent studies indicate a role of excessive interleukin-6 (IL6) signaling in the pathogenesis of schizophrenia. Findings regarding changes in the circulating levels of soluble interleukin-6 receptor (sIL6R) in schizophrenia have been equivocal. The study was performed on a group of 147 trio (patients diagnosed with schizophrenia and their healthy parents). Polymorphisms of IL6 (rs1800795, rs1800797) and IL6R (rs4537545, rs4845617, rs2228145) genes were genotyped with the use of TaqMan SNP Genotyping Assays. No association of the polymorphisms from IL6 and IL6R genes with schizophrenia was found. We also investigated haplotypes in IL6 gene (consisting of rs1800795 and rs1800797) and in IL6R gene (consisting of rs4537545, rs2228145). We also found no preference in transmission of any haplotype. Our results do not support the theory that polymorphisms of IL6 and IL6R genes are involved in the pathogenesis of schizophrenia. It seems advisable to carry out further examinations of the role of these polymorphisms in schizophrenia by means of TDT method and classical (case-control) association method.

FKBP5 polymorphism is associated with major depression but not with bipolar disorder.

BACKGROUND: Altered activity of hypothalamus-pituitary-adrenal glands (HPA) axis in response to stress underlies the pathogenesis of mood disorders such as depression and bipolar disorder. Chaperone proteins regulate sensitivity of glucocorticoid receptor (GR) to steroids. We hypothesized that genetic variants within the FKBP5 - gene encoding co-chaperone protein essential in GR signaling - may influence the susceptibility to major depressive disorder and bipolar disorder. METHODS: In the study participated 528 bipolar patients, 218 patients with major depressive disorder and 742 subjects from control group. Genotypes for eight FKBP5 polymorphisms (rs1360780, rs755658, rs9470080, rs4713916, rs7748266, rs9296158, rs9394309, rs3800373) were established by TagMan SNP Genotyping Assays (Applied Biosystems). Linkage disequilibrium analysis for FKBP5 gene was done in Haploview. Gene-gene interactions between FKBP5 and NR3C1 polymorphisms (reported previously) were analyzed using the multidimensionality-reduction method (MDR). RESULTS: We have observed an association between five FKBP5 polymorphisms (rs1360780, rs9470080, rs4713916, rs9296158 and rs9394309) and major depressive disorder (p=0.011; p=0.007, p=0.038; p=0.030; p=0.018, respectively), but not bipolar disorder. In linkage disequilibrium analysis we found that seven FKBP5 polymorphisms build haplotype block (rs3800373, rs755658, rs9296158, rs7748266, rs1360780, rs9394309, rs9470080, respectively). We observed that two haplotype combinations (ACATTGT and CCACTAT) were significantly more frequent in the MDD patients than in controls (p=0.014 and p=0.043). We have not observed such an association for BD patients. We have found that interaction between rs9470080 of FKBP5 and rs6198 of NR3C1 influences MDD risk. LIMITATIONS: The main limitations of this study include low power and limited sample size of MDD patients. CONCLUSIONS: Single markers and haplotypes of FKBP5 gene and the interaction with glucocorticoid receptor gene (NR3C1) may influence MDD predisposition.