Brain-derived Neurotrophic Factor Rs6265 Polymorphism Research Articles

Abstract 184: Cardioprotective Effects of Brain-derived Neurotrophic Factor rs6265 Polymorphism in Duchenne Cardiomyopathy

We previously identified brain-derived neurotrophic factor (BDNF) as a putative cardiac-specific biomarker for preserved cardiac function in Duchenne Muscular Dystrophy (DMD). BDNF has cardioprotective qualities that may attenuate dilated cardiomyopathy, and a common, functional BDNF single nucleotide polymorphism rs6265 (Val66-Met) may be correlated with increased risk of cardiovascular events. We hypothesized that BDNF is protective in the setting of DMD and that BDNF’s beneficial effects are diminished in rs6265 allelic carriers. We compared circulating BDNF levels with cardiovascular and skeletal muscle functional parameters in DMD patients stratified by carrier status. Positive association of circulating BDNF with left ventricular ejection fraction in DMD patients was restricted to non-carriers of the rs6265 allele, whereas carriers exhibited worse cardiac function with increased BDNF, more fibrosis and worse skeletal muscle function. To more directly assess association of rs6265 with cardiac function, we used mice with knock-in of BDNF polymorphic Val66Met allele. RNASeq showed higher expression of extracellular matrix genes in Val66Met hearts, and there was a negative correlation of cardiac BDNF protein levels with fibrosis. Additionally, there were baseline echocardiographic and ECG differences, and isolated cardiomyocytes had decreased contractility. This overall cardiac phenotype was substantially enhanced when Val66Met mice were crossed with muscular dystrophy mice. Considered together, our results indicate that BDNF plays a protective role in the dystrophic heart and may represent a novel therapeutic candidate for DMD cardiomyopathy.

Association of the carriage of IL-1B rs1143634 and rs16944 polymorphisms and BDNF rs6265 polymorphism with temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is one of the most common and refractory forms of epilepsy, which has different etiologies. Experimental and clinical studies have demonstrated that transformation of the normal brain neuron activity pattern into paroxysmal one is accompanied by changes in the expression of cytokines and neurotrophins in the hippocampus and temporal cortex. Modulation of the expression of brainderived neurotrophic factor (BDNF) may be associated with the carriage of the single nucleotide polymorphism (SNP) rs6265 in the BDNF gene. Groups of investigators have shown the increased expression of BDNF in the hippocampus and temporal cortex of patients with drugresistant epilepsy. Independent studies have demonstrated the role of the IL-1B gene encoding the proinflammatory cytokine interleukin (IL) 1in the development of inflammatory responses and structural mediobasal TLE with hippocampal sclerosis. Objective: to study the association of the carriage of the SNPs rs16944 and rs1143634 in the IL-1B gene and rs6265 in the BDNF gene with the development of TLE. Patients and methods. Real-time polymerase chain reaction was used to conduct a molecular genetic study of the carriage of the SNPs rs1143634 and rs16944 in the IL-1B gene and rs6265 in the BDNF gene in 84 patients with TLE and in 203 healthy Caucasian volunteers, who lived in the Siberian Federal District. Results and discussion. The carriage of the high-producing C allele (odds ratio (OR)=2.01; 95% confidence interval (CI), 1.31–3.08; p=0.001) and the homozygous CC genotype (OR=2.48; 95% CI, 1.47–4.17; p=0.001) of SNP rs1143634 in the IL-1B gene was found to be statistically significantly associated with the development of TLE in the examined population. There were no statistically significant differences in the carriage of the SNPs rs1143634 and rs16944 in the IL-1B gene and rs6265 in the BDNF gene with the clinical presentations and course of TLE (p>0.05). The carriage of the SNP rs6265 in the BDNF gene was ascertained to be unassociated with the development of TLE (2=0.3; p =0.86). Conclusion . The authors have established an association of the carriage of the high-producing C allele and the homozygous CC genotype of the SNP rs1143634 in the IL-1B gene with TLE.

BDNF and NGF gene polymorphisms and urine BDNF–NGF levels in children with primary monosymptomatic nocturnal enuresis

The pathophysiology and genetic influences in nocturnal enuresis have not been fully elucidated. Delayed neuronal maturation has been suggested as a pathogenetic mechanism in primary monosymptomatic nocturnal enuresis (PMNE). Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are neurotrophins affecting maturation of the nervous system. The aim of this preliminary study was to investigate BDNF and NGF gene polymorphisms and urine levels of BDNF and NGF in children with PMNE as a first time. The single-nucleotide polymorphisms of BDNF (rs6265:G>A:Val66Met; rs8192466:C>T:Thr2Ile) and NGF (rs6330:C>T:Ala35Val, rs11466112:C>T:Arg221Trp) were investigated by comparing 104 children with PMNE and 140 healthy control subjects. Children with non-PMNE were excluded. DNA isolation and detection of polymorphisms were performed by real-time polymerase chain reaction. In addition, urine BDNF and NGF levels of 47 PMNE and 29 healthy children were measured by enzyme-linked immunosorbent assay method and normalized to urine creatinine (Cr) concentration for comparisons. There were no differences in genotype and allele frequencies of BDNF rs6265 and NGF rs6330 polymorphisms between patients with PMNE and the control group (P>0.05). No mutant alleles were found in BDNF rs8192466 and NGF rs11466112 polymorphisms in either group. Children with PMNE had higher urine BDNF/Cr (0.020±0.010 vs 0.010±0.002; P=0.008) and NGF/Cr ratio (3.01±1.87 pg/mg vs 1.77±0.26 pg/mg; P=0.002) compared with the control subjects. However, no significant differences were found in BDNF/Cr and NGF/Cr values between GG, GA, and AA genotypes of BDNF rs6265 polymorphismand CC and CT genotypes of NGF rs6330 polymorphism (P>0.05). In this study, no association of BDNF and NGF gene polymorphisms with PMNE was found, and urine neurotrophin concentrations were not directly influenced by investigated polymorphisms. Although, previously increased urine neurotrophin secretion has been found in detrusor overactivity, bladder inflammation, and dysfunctional voiding, this preliminary results also showed an increase in neurotrophins in PMNE.Higher urine neurotrophin levels may be related to delayed and continued neuronal maturation or increased production of neurotrophins in the bladder. The increased urine neurotrophins in PMNE may be an indicator of increased sensory nerve excitability of the bladder, contributing to the development of enuresis. This study showed that investigated neurotrophin gene polymorphisms did not make a significant contribution to the development of PMNE, but urine levels of neurotrophin gene products were higher in PMNE. Owing to the complexity and heterogeneity of genotype-phenotype relationships in enuresis, further studies are needed in PMNE.

Functional rs6265 polymorphism in the brain‐derived neurotrophic factor gene confers protection against neurocognitive dysfunction in posttraumatic stress disorder among Chinese patients with hepatocellular carcinoma

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that plagues trauma survivors. Evidence shows that brain-derived neurotrophic factor (BDNF) may be involved in the occurrence and development of PTSD. Here we tried to demonstrate whether BDNF gene polymorphisms are correlated with neurocognitive function following PTSD in patients with hepatocellular carcinoma (HCC). This study included 102 patients withHCC complicated with PTSD, 146 HCC patients, and 152 healthy volunteers. Initially, we evaluated the neurocognitive function of the study subjects. Next, we measured BDNF G11757C and rs6265 polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. The correlation of BDNF polymorphisms and BDNF level with HCC complicated with PTSD was evaluated. The results revealed that HCC complicated with PTSD showed decreased serum BDNF level and Mini-mental state examination (MMSE) score. Serum BDNF level of HCC and HCC complicated with PTSD was positively correlated with MMSE score. GA + AA allele and A allele of rs6265 increased the risk of PTSD among patients with HCC. GA and AA genotypes of rs6265 were correlated with the decreased MMSE score of HCC complicated with PTSD. Haplotype GA of rs6265 and G11757C increased the risk of PTSD for HCC, while haplotype CG decreased this risk. Lastly, the logistic regression analysis suggested that low BDNF level was a contributor to HCC complicated with PTSD, while GG genotype of rs6265 served as a protective factor. Collectively, this study defines the GG genotype of BDNF rs6265 polymorphism as a protector to HCC complicated with PTSD. In addition, these results provided a promising target for PTSD prevention in patients with HCC.

BDNF rs6265 (Val66Met) Polymorphism as a Risk Factor for Blepharospasm.

A few genetic variants are implicated in the development of blepharospasm (BSP). The precise role of the rs6265 on the brain-derived neurotrophic factor (BDNF) gene on BSP remains controversial. The effect of rs6265 on BSP was evaluated. 206 patients with BSP and 206 healthy controls were recruited and genotyped for the rs6265. We also performed a meta-analysis, by pooling our results with those from previous studies. A significant effect of rs6265 on the risk of BSP was found in the dominant model of inheritance [odds ratio (OR) (95% confidence interval (CI) 1.52 (1.01-2.29), p = 0.044]. Mutational load analysis of rs6265 in the risk of BSP using the ORG revealed that higher load of the "A" allele of rs6265 denotes higher probability of a subject to develop BSP (ORG 1.48; 95% CI 1.00-2.19). Finally, pooled results from the meta-analysis revealed that the rs6265 is associated with an increased risk of BSP in the dominant model [OR 1.26; 95% CI 1.02-1.55, pz = 0.03]. Also, higher load of the "A" allele of rs6265 denotes higher probability of a subject to develop BSP (ORG 1.26; 95% CI 1.04-1.53). The present study provides additional evidence to the existing knowledge concerning the contribution of the rs6265 BDNF on the risk of developing BSP. While the pathophysiology and genetic susceptibility in BSP and focal dystonia are only partially understood, it seems that BDNF and rs6265 may constitute one essential risk factor that is heavily involved.

Human BDNF rs6265 polymorphism as a mediator for the generalization of contextual anxiety.

The Met allele of the human brain-derived neurotrophic factor (BDNF) gene might be a risk factor for anxiety disorders and is associated with reduced hippocampal volume. Notably, hippocampus plays a crucial role in contextual learning and generalization. The role of the BDNF gene variation in human context-conditioning and generalization is still unknown. We investigated 33 carriers of the Met allele (18 females) and 32 homozygous carriers of the Val allele (15 females) with a virtual-reality context-conditioning paradigm. Electric stimulations (unconditioned stimulus, US) were unpredictably delivered in one virtual office (CTX+), but never in another virtual office (CTX-). During generalization, participants revisited CTX+ and CTX- and a generalization office (G-CTX), which was a mix of the other two. Rating data indicated successful conditioning (more negative valence, higher arousal, anxiety and contingency ratings for CTX+ than CTX-), and generalization of conditioned anxiety by comparable ratings for G-CTX and CTX+. The startle data indicated discriminative learning for Met allele carriers, but not for Val homozygotes. Moreover, a trend effect suggests that startle responses of only the Met carriers were slightly potentiated in G-CTX versus CTX-. In sum, the BDNF polymorphism did not affect contextual learning and its generalization on a verbal level. However, the physiological data suggest that Met carriers are characterized by fast discriminative contextual learning and a tendency to generalize anxiety responses to ambiguous contexts. We propose that such learning may be related to reduced hippocampal functionality and the basis for the risk of Met carriers to develop anxiety disorders.

BDNF rs6265 polymorphism methylation in Multiple Sclerosis: A possible marker of disease progression.

IntroductionBrain-Derived Neurotrophic Factor (BDNF) and its most common polymorphism Val66Met are known to have a role in Multiple Sclerosis (MS) pathogenesis. Evidence is accumulating that there is an involvement of DNA methylation in the regulation of BDNF expression. The aim of this study was to assess in blood samples of MS patients the correlation between the methylation status of the CpG site near BDNF-Val66Met polymorphism and the severity of the disease.MethodsWe recruited 209 MS patients that were genotyped for the BDNF Val66Met polymorphism. For each patient we quantitatively measured the methylation level of cytosine included in the exonic CpG site that can be created or abolished by the Val66Met BDNF polymorphism. Furthermore, we analyzed the clinical history of each patient and determined the time elapsed since the onset of the disease and an EDSS score of 6.0.ResultsThe genetic analysis identified 122 (58.4%) subjects carrying the Val/Val genotype, 81 (38.8%) with Val/Met genotype, and 6 (2.8%) carrying the Met/Met genotype. When the endpoint of an EDSS score of 6 was taken into account by means of a survival analysis, 52 failures (i.e., reaching an EDSS score of 6) were reported. When the sample was stratified according to the percentage of the BDNF methylation, subjects falling below the median (median methylation = 81%) were at higher risk of failure (IRD = 0.016; 95%CI = 0.0050–0.0279; p = 0.004).ConclusionsIn patients with a high disease progression the hypomethylation of the BDNF gene could increase the secretion of the protective neurotrophin, so epigenetic modifications could be the organism response to limit a brain functional reserve loss. Our study suggests that the percentage of methylation of the BDNF gene could be used as a prognostic factor for disease progression toward a high disability in MS patient.

The association study between the polymorphisms of BDNF gene and the response of citalopram antidepressant treatment

Objective To investigate the relevance of brain-derived neurotrophic factor (BDNF) gene polymorphisms and the effects of citalopram antidepressant. Methods The subjects comprised 280 patients according to the diagnostic and statistical manual of mental disorders in the fourth edition (DSM-IV) criterion for major depressive disorder (MDD). Severity of depression were assessed by 17 Hamilton depression scale (HAMD) at the baseline and 1, 2, 4, 6 weekend.Citalopram were selected for treatment.Polymerase chain reaction (PCR) and DNA sequencing analysis were used to detect the genotype of SNPs rs7124442 and rs6265 of BDNF.SPSS17.0 software was used for statistical analysis. Results (1) There were 280 patients (242 responders and 38 nonresponders; 175 remissioners and 105 nonremissioners) accomplished 6 weeks of treatment.No association was found between the polymorphisms and antidepressant drug response or remission (the reduction rate of HAMD score ≥50% was defined as response, conversely, defined as nonresponse; HAMD score more than 7 was named as remission, in contrast, named as nonremission) (P>0.05). (2) Repeated measures analysis of variance was adopted to compare the change of HAMD scores among the genotypes at different time points.There was a significant difference in rs6265 polymorphism between the GA+ AA genotype (the scores of HAMD at 2, 4, 6 weeks were(9.98±4.97), (8.02±4.50), (5.83±3.49) respectively) and the GG genotype groups (the scores of HAMD at 2, 4, 6 weeks were(11.90±6.55), (9.34±4.71), (7.07±4.28) respectively) (P=0.031). Conclusion The results suggest that BDNF rs6265 polymorphisms in part determine the antidepressant response to citalopram. Key words: Major depressive disorders; Brain-derived neurotrophic factor; Gene polymorphisms; Citalopram; Antidepressant treatment

Dose-dependent genotype effects of BDNF Val66Met polymorphism on default mode network in early stage Alzheimer's disease.

In humans, brain-derived neurotrophic factor (BDNF) has been shown to play a pivotal role in neurocognition, and its gene contains a functional polymorphism (Val66Met) that may explain individual differences in brain volume and memory-related activity.In this study, we enrolled 186 Alzheimer's disease (AD) patients who underwent 3D T1 magnetic resonance imaging, and explored the gray matter (GM) structural covariance networks (SCN). The patients were divided into three groups according to their genotype: Met/Met (n = 45), Val/Met (n = 86) and Val/Val (n = 55). Seed-based analysis was performed focusing on four SCN networks. Neurobehavioral scores served as the major outcome factor.Only peak cluster volumes of default mode medial temporal lobe network showed significant genotype interactions, of which the interconnected peak clusters showed dose-dependent genotype effects. There were also significant correlations between the cognitive test scores and interconnected-cluster volumes, especially in the orbitofrontal cortex.These findings support the hypothesis that BDNF rs6265 polymorphisms modulate entorhinal cortex-interconnected clusters and the valine allele was associated with stronger structural covariance patterns that determined the cognitive outcomes.

The Association of Brain-Derived Neurotrophic Factor Gene Polymorphism with Obstructive Sleep Apnea Syndrome and Obesity.

Obesity represents a major risk factor for Obstructive Sleep Apnea Syndrome (OSAS). Brain-derived neurotrophic factor (BDNF) affects the mechanisms that regulate weight, eating behavior, and metabolism. This project aims to investigate the possible association of BDNF gene polymorphism with obesity and OSAS, and to contribute knowledge to the understanding of the pathophysiology of OSAS. The subjects included in this study were selected among the individuals who were hospitalized in the Erciyes University Medical School Chest Diseases Sleep Medicine Laboratory. Subjects were divided into four groups based on the presence of OSAS and/or obesity. Group 1 included OSAS+ obesity+ patients, Group 2 included OSAS+ obesity- patients, Group 3 included OSAS- obesity+ patients, and Group 4 included OSAS- obesity- patients. The targeted patient number per each study group was 45, but only 32 patients could be enrolled into Group 3. Out of a total number of 167 subjects, 117 (70.1%) had BDNF 196G/G, 48 (28.7%) had BDNF 196G/A, and 2 (1.2%) had BDNF 196A/A genotype. Of 48 subjects having BDNF 196G/A genotype, 32 (66.6%) were obese, and 16 (33.3%) were non-obese. Out of 90 subjects with OSAS, 64 (71.1%) had BDNF 196G/G, and 25 (27.8%) had BDNF 196G/A genotype. Out of 77 subjects without OSAS, BDNF 196G/G, and BDNF 196G/A genotypes were detected in 53 (68.8%) and 23 (29.9%) subjects, respectively. A statistically significant difference was demonstrated between the four study groups in terms of BDNF rs6265 polymorphism (p=0.013). This difference was attributed to OSAS+ obesity- Group, in which BDNF 196G/G genotype was more common and BDNF 196G/A polymorphism was less common than the patients in other groups. In conclusion, BDNF 196G/A genotype was found to be more frequent among obese patients compared to the non-obese individuals, but it was not significantly related to OSAS in the present study. BDNF196G/G genotype was more common and BDNF 196G/A polymorphism was less common among OSAS+ obesity- subjects compared to the other study groups.

Depression in multiple sclerosis: effect of brain derived neurotrophic factor Val66Met polymorphism and disease perception

Depression is common amongst subjects with multiple sclerosis (MS), and several investigations have explored different determinants of this condition, including physical disability, psychological and psychosocial factors. The brain derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with depression. The aim of this study was to analyze the influence of disease-related factors, BDNF Val66Met polymorphism and perception of disease on the severity of depression in MS. In total, 136 MS patients (88 women) were recruited and genotyped for BDNF rs6265 polymorphism at nucleotide 196 (G/A) using 'high resolution melting'. Depressive symptoms were assessed by the Multiple Sclerosis Depression Rating Scale. Perception of health status was assessed using the SF-36 questionnaire. A multivariable linear regression model showed that the best predictors of depression were the SF-36 General health (β = -0.209; P = 0.013), Mental health (β = -0.410; P < 0.001) and Social activity (β = -0.195; P = 0.035) scores; physical disability (assessed by the Extended Disability Status Scale score) was directly correlated to depression severity on univariate analysis, but it was not a relevant predictor of depression on multivariate analysis; other variables directly related to the disease (treatment, annual relapsing rate) and the BDNF Val66Met polymorphism were not significantly associated with depression. Perception of the health status is the principal predictor of depressive symptoms in our sample. This result supports the hypothesis that the subjective interpretation of the disease's consequences is one of the main factors in determining depression in MS.

NRSF and BDNF polymorphisms as biomarkers of cognitive dysfunction in adults with newly diagnosed epilepsy.

Cognitive dysfunction is a common comorbidity in people with epilepsy, but its causes remain unclear. It may be related to the etiology of the disorder, the consequences of seizures, or the effects of antiepileptic drug treatment. Genetics may also play a contributory role. We investigated the influence of variants in the genes encoding neuron-restrictive silencer factor (NRSF) and brain-derived neurotrophic factor (BDNF), proteins previously associated with cognition and epilepsy, on cognitive function in people with newly diagnosed epilepsy. A total of 82 patients who had previously undergone detailed neuropsychological assessment were genotyped for single nucleotide polymorphisms (SNPs) across the NRSF and BDNF genes. Putatively functional SNPs were included in a genetic association analysis with specific cognitive domains, including memory, psychomotor speed, and information processing. Cross-sectional and longitudinal designs were used to explore genetic influences on baseline cognition at diagnosis and change from baseline over the first year since diagnosis, respectively. We found a statistically significant association between genotypic variation and memory function at both baseline (NRSF: rs1105434, rs2227902 and BDNF: rs1491850, rs2030324, rs11030094) and in our longitudinal analysis (NRSF: rs2227902 and BDNF: rs12273363). Psychomotor speed was also associated with genotype (NRSF rs3796529) in the longitudinal assessment. In line with our previous work on general cognitive function in the healthy aging population, we observed an additive interaction between risk alleles for the NRSF rs2227902 (G) and BDNF rs6265 (A) polymorphisms which was again consistent with a significantly greater decline in delayed recall over the first year since diagnosis. These findings support a role for the NRSF–BDNF pathway in the modulation of cognitive function in patients with newly diagnosed epilepsy.

Interaction between BDNF rs6265 Met allele and low family cohesion is associated with smaller left hippocampal volume in pediatric bipolar disorder

BackgroundGenetic and environmental factors are implicated in the onset and evolution of pediatric bipolar disorder, and may be associated to structural brain abnormalities. The aim of our study was to assess the impact of the interaction between the Brain-Derived Neurotrophic Factor (BDNF) rs6265 polymorphism and family functioning on hippocampal volumes of children and adolescents with bipolar disorder, and typically-developing controls. Methods: We evaluated the family functioning cohesion subscale using the Family Environment Scale-Revised, genotyped the BDNF rs6265 polymorphism, and performed structural brain imaging in 29 children and adolescents with bipolar disorder, and 22 healthy controls. Results: We did not find significant differences between patients with BD or controls in left or right hippocampus volume (p=0.44, and p=0.71, respectively). However, we detected a significant interaction between low scores on the cohesion subscale and the presence of the Met allele at BNDF on left hippocampal volume of patients with bipolar disorder (F=3.4, p=0.043). None of the factors independently (BDNF Val66Met, cohesion scores) was significantly associated with hippocampal volume differences. Limitations: small sample size, cross-sectional study. Conclusions: These results may lead to a better understanding of the impact of the interaction between genes and environment factors on brain structures associated to bipolar disorder and its manifestations.

Association BetweenBDNFGene Polymorphisms and Attention Deficit Hyperactivity Disorder in Korean Children

Attention deficit hyperactivity disorder (ADHD) is a common childhood neuropsychiatric disorder characterized by behavioral problems such as attention deficit, hyperactivity, and impulsivity. The brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain. The aim of the present study was to investigate the association between the genotype and alleles for the BDNF gene in Korean children with ADHD. The sample consisted of 180 ADHD children and 159 control children. We diagnosed ADHD according to the DSM-IV. ADHD symptoms were evaluated with Conners' Parent Rating Scales and Dupaul Parent ADHD Rating Scales. Blood samples were taken from the 339 subjects, DNA was extracted from blood lymphocytes, and polymerase chain reaction was performed for BDNF rs6265, rs11030101, rs10835210, rs7103873, and rs2030324 polymorphisms. Alleles and genotype frequencies were compared using the Chi-square test. We compared the allele and genotype frequencies of the BDNF gene polymorphism in the ADHD and control groups. This study showed that there was a significant correlation among the allele frequencies of the rs11030101 and rs10835210 single nucleotide polymorphisms (SNPs) (odds ratio=0.61, 95% confidence interval=0.39-0.96, p=0.034), but the final conclusions are not definite. Follow-up studies with larger patient or pure subgroups are expected. These results suggest that the BDNF allelic structure may impact ADHD symptoms.

Combined effects of the BDNF rs6265 (Val66Met) polymorphism and environment risk factors on psoriasis vulgaris.

Smoking, alcohol consumption and higher body mass index (BMI) are well established risk factors for psoriasis and also associated with the clinical traits of the disease. And the genetic influences on these three risk factors indeed exist. Previously studies have demonstrated these risk factors related genetic variants may also play a role in the development of risk factors-related diseases. Then we performed a hospital-based study in order to evaluate the combined effect of the risk factors and their related polymorphism rs6265 in brain-derived neurotrophic factor (BDNF) gene on psoriasis vulgaris (PV) risk and clinic traits. The case-control study involved 660 subjects including 345 cases and 315 controls in Chinese Han population. The variant of rs6265 was typed by SNaPshot Multiplex Kit (Applied Biosystems Co., USA). We confirmed that higher BMI (≥25), smoking and alcohol consumption were risk factors for PV, and the estimated ORs were 1.63(95 % confidence interval (CI); 1.12-2.37), 2.09(95 % CI; 1.44-3.03) and 1.65(95 % CI; 1.15-2.37) respectively. Genotype and allele distributions did not differ significantly between case and control. However, we found combined effect of rs6265 genotype (GG) and higher BMI (≥25) increased risk of PV (OR = 2.09; 95 % CI, 1.02-4.28; P < 0.05; adjusted OR = 3.19; 95 % CI, 1.37-7.45; P < 0.05) and clinically severity of PV (OR = 2.71; 95 % CI, 1.09-6.72; P < 0.05; adjusted OR = 1.25; 95 % CI, 1.10-1.40; P < 0.05). But none such significant combined effect was observed between others genotype (AA and AG) and other risk factors. In conclusions, the combined effect of BDNF rs6265 genotype (GG) and higher BMI may increases the risk and clinical severity of PV in Chinese Han population.

MiRNA-206 and BDNF genes interacted in bipolar I disorder

BackgroundSeveral lines of evidence have suggested that has-mir-206 (miRNA-206) may regulate brain-derived neurotrophic factor (BDNF) protein synthesis. The primary aim of this study was to determine whether miRNA-206 gene (MIR206) may confer susceptibility to bipolar disorder type I (BD-I) and treatment response to mood stabilizers. Also, we intended to verify the hypothesis that a potential interplay of MIR206 and BDNF may influence the genetic risk for BD-I and treatment response. MethodsThe MIR206 rs16882131 and BDNF rs6265 polymorphisms were genotyped in 280 BD-I patients and 288 healthy controls. Treatment response to lithium and valproate was retrospectively determined. ResultsNo association was observed in the individual polymorphism with regards to risk of BD-I and treatment response. Our results showed a significant gene to gene interaction between the MIR206 rs16882131 and BDNF rs6265 polymorphisms that contribute to BD-I susceptibility and treatment response. Further analysis showed a significant interaction between MIR206 and BDNF on treatment score (F3, 138=8.61, P=0.046), and individuals with MIR206 T/T+TC and BDNF A/A genotypes had a significantly lower mean treatment score than those with MIR206 CC and BDNF A/A+A/G as well as those with MIR206 CC and BDNF G/G genotypes (P=0.018 and 0.013, respectively). LimitationThis is a preliminary investigation with relatively small sample size. ConclusionOur findings provide initial evidence of the gene-to-gene interaction of MIR206 and BDNF in regards to the risk for BD-I as well as treatment response to mood stabilizers.

Poster #T8 EFFICACY AND SAFETY OF OLANZAPINE LONG-ACTING INJECTION IN PATIENTS WITH SCHIZOPHRENIA: A POST-HOC ANALYSIS OF A 6-YEAR MULTINATIONAL SINGLE-ARM OPEN-LABEL STUDY

Genetic and environmental factors are implicated in the onset and evolution of pediatric bipolar disorder, and may be associated to structural brain abnormalities. The aim of our study was to assess the impact of the interaction between the Brain-Derived Neurotrophic Factor (BDNF) rs6265 polymorphism and family functioning on hippocampal volumes of children and adolescents with bipolar disorder, and typically-developing controls. Methods: We evaluated the family functioning cohesion subscale using the Family Environment Scale-Revised, genotyped the BDNF rs6265 polymorphism, and performed structural brain imaging in 29 children and adolescents with bipolar disorder, and 22 healthy controls. Results: We did not find significant differences between patients with BD or controls in left or right hippocampus volume (p=0.44, and p=0.71, respectively). However, we detected a significant interaction between low scores on the cohesion subscale and the presence of the Met allele at BNDF on left hippocampal volume of patients with bipolar disorder (F=3.4, p=0.043). None of the factors independently (BDNF Val66Met, cohesion scores) was significantly associated with hippocampal volume differences. Limitations: small sample size, cross-sectional study. Conclusions: These results may lead to a better understanding of the impact of the interaction between genes and environment factors on brain structures associated to bipolar disorder and its manifestations.

The BDNF Val66Met Polymorphism Modulates the Generalization of Cued Fear Responses to a Novel Context

Brain-derived neurotrophic factor (BDNF) has a crucial role in activity-dependent synaptic plasticity and learning and memory. The human functional single-nucleotide BDNF rs6265 (Val66Met) polymorphism has been found to be associated with alteration in neural BDNF release and function correlating with altered emotional behavior. Here, we investigated for the first time the hypothesis that this polymorphism in humans modulates the context dependency of conditioned fear responses. Applying a new paradigm examining generalization of cued fear across contexts, 70 participants stratified for BDNF Val66Met polymorphism were guided through two virtual offices (context) in which briefly illuminated blue and yellow lights served as cues. In the fear context, one light (conditioned stimulus, CS+) but not the other light (CS-) was associated with an electric shock (unconditioned stimulus, US). In the safety context, both lights were presented too, but no US was delivered. During the test phase, lights were presented again both in learning contexts and in a novel generalization context without any US. All participants showed clear fear conditioning to the CS+ in the fear context as indicated by potentiation of startle responses and reports of fear. No fear reactions were found for the CS+ in the safety context. Importantly, generalization of fear responses indicated by the potentiation of startle response to the CS+ compared with the CS- in the novel context was evident only in the Met-carrying group. These are the first results to provide evidence in humans that BDNF modulates the generalization of fear responses. Such context-dependent generalization processes might predispose Met carriers for affective and anxiety disorders.

P.1.a.025 Age at onset of depressive disorder is associated with interaction of BDNF rs6265 and 5-HTTLPR polymorphism

Based on biological interactions between the serotonergic system and the brain-derived neurotrophic factor (BDNF), BDNF is a plausible candidate for a gene–gene–environment interaction moderating the interaction between the s/l- promoter polymorphism of the serotonin transporter (5-HTTLPR) and childhood abuse. We tested the hypothesis of a three-way interaction with respect to depressive symptoms.2035 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and the Childhood Trauma Questionnaire. All subjects were genotyped for the BDNF Val66Met (rs6265) and the s/l 5-HTTLPR polymorphisms.Tobit regression analyses revealed a three-way-interaction between the three genotypes of 5-HTTLPR and the BDNF genotypes and overall childhood abuse for the BDI-II score (p = 0.02). Emotional abuse carried the main effect of the interaction (p = 0.008). The s/s genotype of the 5-HTTLPR exerted its negative impact on mental health after childhood abuse only in the presence of the BDNF Val/Val genotype but not in the presence of the BDNF Met allele. In contrast, the l allele of the 5-HTTLPR also emerged as a genetic risk factor for depression in carriers of one or two Met alleles.Our results point to a gene–gene–environment interaction that relevantly impacts on the role of the s/s genotype of the 5-HTTLPR in childhood abuse: Depending on the BDNF background (Val/Val versus Met allele) the s/s genotype showed either protective or risk properties with regard to depressive symptoms.

Polymorphisms of brain-derived neurotrophic factor associated with heroin dependence

Brain-derived neurotrophic factor (BDNF) promotes synaptic remodeling and modulates the function of other neurotransmitters. It also plays a role in the reward response to many drugs, including heroin. To identify genetic variants associated with heroin dependence, we compared four single nucleotide polymorphisms (SNPs, rs13306221, rs6265, rs56164415, and rs16917204) of the BDNF gene in 487 subjects with heroin dependence and 492 healthy individuals. The analysis revealed the G allele of rs6265 was significantly more common in heroin-dependent subjects than in the healthy controls (P=0.001 after Bonferroni correction). Among heroin-dependent individuals, the onset of dependence was significantly earlier in individuals with GG or GA genotypes compared to AA individuals (P<0.01). Additionally, we found that the G allele of rs13306221 was significantly more frequent in heroin-dependent subjects than in controls (P=0.005 after Bonferroni correction). These findings support a role of BDNF rs6265 and rs13306221 polymorphisms in heroin dependence and may guide future studies to identify other genetic risk factors for heroin dependence.