[The association of single-nucleotide polymorphism rs6265 of the brain-derived neurotrophic factor gene with clinical features in Parkinson's disease]. / Assotsiatsiya odnonukleotidnogo polimorfizma rs6265 gena neirotroficheskogo faktora golovnogo mozga s osobennostyami klinicheskoi kartiny bolezni Parkinsona.

OBJECTIVE: To evaluate the frequency and severity of various clinical symptoms of Parkinson's disease (PD) depending on the BDNF rs6265 polymorphism. MATERIAL AND METHODS: The study included 533 patients with PD. The stage of PD was assessed using the Hoehn and Yahr scale (1967), motor symptoms were evaluated with MDS-UPDRS. Assessment of non-motor symptoms (NMS) in PD was conducted using the Beck Depression Inventory II (BDI-II); the Hospital Anxiety and Depression Scale (HADS); the Apathy Scale; the Montreal Cognitive Assessment (MoCA test); the Questionnaire for Impulsive-Compulsive Disorders in PD -Rating Scale (QUIP-RS). Genotyping of the BDNF variant (rs6265) was performed using real-time PCR with TaqMan probes. RESULTS: Most PD patients have a combination of NMS increasing as the disease progresses and is determined by molecular-genetic individual characteristics. There are significant differences in the severity of motor symptoms and NMS: individuals with the AA genotype showed significantly pronounced motor symptoms (p<0.0001); emotional-affective symptoms (p<0.0001); cognitive and impulsive behavioral disorders (p<0.0001). CONCLUSION: The rs6265 BDNF allele A is associated with a wide range of NMS, increasing the risk of their development in patients with PD, thus playing the important role in the etiopathogenesis of this pathology.

[The relationship between the rs6265 polymorphism of the BDNF gene and the level of serum neurotrophic factor in patients with Parkinson's disease]. / Svyaz' polimorfizma rs6265 gena BDNF s urovnem syvorotochnogo neirotroficheskogo faktora u patsientov s bolezn'yu Parkinsona.

OBJECTIVE: To evaluate the clinical features and the level of serum brain-derived neurotrophic factor (BDNF) in groups of patients with Parkinson's disease (PD) differentiated by the genotypes of BDNF polymorphism (rs6265). MATERIAL AND METHODS: The level of serum BDNF in the biomarkers' multiplex panel of neurodegenerative diseases (HNDG3MAG-36K) was assessed in 134 PD patients. Allele discrimination was carried out by real-time PCR using TaqMan probes for the analysis of BDNF rs6265 polymorphism in groups of patients and controls (n=192) matched for sex, age and ethnicity. RESULTS: Comparing the distribution of rs6265 genotypes and alleles between groups of patients and controls no significant differences were found (p>0.05). Serum BDNF levels varied significantly by genotype (rs6265) among PD patients. Minimum mean serum BDNF level (320.1±164.6 pg/ml) was noted for individuals with the AA genotype, which significantly differs from the corresponding indicator among individuals with GA (2944.2±1590.6 pg/ml; p=0.0001) and GG genotypes (2949.4±1620.6 pg/ml; p=3.9×10-5). The concentration of BDNF significantly differed between patients with different forms of PD (p=0.0007) and increased as the stage of the disease progressed according to Hoehn and Yahr staging scale (p=1.0×10-6). CONCLUSION: The BDNF rs6265 polymorphism was not associated with the development of PD in the studied population. The variability of the mean serum BDNF level was established depending on the genotype of the BDNF polymorphism in PD patients and a number of clinical features.

BDNF rs962369 Is Associated with Major Depressive Disorder.

This study enrolled 291 patients diagnosed with depression and schizophrenia (F32, F33, and F20 according to ICD-10) and 227 ethnicity-matched control subjects. We analyzed the distribution of BDNF rs6265 and BDNF rs962369 genotypes, finding no significant associations between these and schizophrenia. We revealed a significant increase in the risk of single-episode major depression disorder (MDD) for rs962369 minor allele homozygotes (CC vs. TT+TC), an association that persisted after adjusting for age and sex (OR 3.47; 95% CI 1.36-8.85; p = 0.009). Furthermore, rs962369 genotype was significantly associated with an increased risk of recurrent MDD in a log-additive model (OR per C-allele 1.65; 95% CI 1.11-2.45; p = 0.013). A comparative analysis between MDD subtypes and between MDD subtypes and schizophrenia showed no significant differences for BDNF rs6265. Notably, the frequency of minor allele C of BDNF rs962369 varied across subgroups, with the highest frequency in patients with recurrent MDD (0.32) and the lowest in schizophrenia patients (0.20). The presence of genotypes with at least one minor allele C was significantly higher in the recurrent MDD patient group compared to the schizophrenia group. In conclusion, the BDNF rs962369 variant was associated with MDD but not with schizophrenia.

High blood levels of brain-derived neurotrophic factor (BDNF) mRNA in early psychosis are associated with inflammatory markers.

The brain-derived neurotrophic factor (BDNF) single nucleotide polymorphism (SNP) rs6265C > T, Val66Met, affects BDNF secretion and has been related to inflammatory processes. Both the rs6265 and BDNF protein levels have been widely investigated in neuropsychiatric disorders with conflicting results. In the present study we examined BDNF mRNA expression in blood considering the SNP rs6265 and its relationship with inflammatory markers in the early stages of psychosis. The rs6265 genotype and blood BDNF mRNA levels were measured in 34 at-risk mental states (ARMS) individuals, 37 patients with first-episode psychosis (FEP) and 42 healthy controls (HCs) by quantitative PCR and reverse transcription (RT)-qPCR using validated TaqMan assays. We also obtained measures of interleukin-6 (IL6) mRNA levels, fibrinogen, neutrophil-to-lymphocyte ratio (NLR) and high-sensitivity C-reactive protein. We identified that BDNF mRNA levels were associated with the rs6265 genotype in an allele-dose-dependent manner, with low expression levels associated with the T allele (Met substitution). Thus, we controlled for the rs6265 genotype in all analyses. Blood BDNF mRNA levels differed between diagnostic groups: patients with FEP exhibited higher blood BDNF mRNA levels than ARMS individuals, and the lowest levels were observed in HC. In addition, we observed significant correlations between BDNF mRNA levels and inflammatory markers (IL6 mRNA levels and NLR), controlled by the rs6265 genotype, in ARMS and FEP groups. This exploratory study suggests that the rs6265 genotype is associated with differential blood mRNA expression of BDNF that increases with illness progression and correlated with inflammation in the early stages of psychosis.

Association Study of BDNF, SLC6A4, and FTO Genetic Variants with Schizophrenia Spectrum Disorders.

Schizophrenia spectrum disorders (patients with a diagnosis of schizophrenia, schizotypal, and delusional disorders: F20-F29 according to International Classification of Diseases 10th revision (ICD-10)) are considered highly heritable heterogeneous psychiatric conditions. Their pathophysiology is multifactorial with involved dysregulated serotonergic neurotransmission and synaptic plasticity. The present study aimed to evaluate the association of SLC6A4 (5-HTTLPR), FTO (rs9939609), and BDNF (rs6265, rs962369) polymorphisms with schizophrenia spectrum disorders in Slovak patients. We analyzed the genotypes of 150 patients with schizophrenia, schizotypal, and delusional disorders and compared them with genotypes from 178 healthy volunteers. We have found a marginally protective effect of LS + SS genotypes of 5-HTTLPR variant of the serotonin transporter SLC6A4 gene against the development of schizophrenia spectrum disorders, but the result failed to remain significant after Bonferroni correction. Similarly, we have not proven any significant association between other selected genetic variants and schizophrenia and related disorders. Studies including a higher number of subjects are warranted to reliably confirm the presence or absence of the studied associations.

Association of polymorphisms rs4680 of the Catechol-O-Methyltransferase gene and rs6265 of the brain derived neurotrophic factor gene with the behavioral inhibition and behavioral activation systems.

Background: The Behavioral Inhibition System (BIS) comprises limbic circuitry implicated in avoidance behaviors. Its increased activation has been identified as a risk factor for anxiety and depressive disorders. In addition, both Catechol-O-Methyltransferase (COMT) and Brain Derived Neurotrophic Factor (BDNF) have been postulated as candidate genes that constitute a vulnerability for the onset of anxiety and depressive disorders. The aim of this study was to evaluate the possible association between the rs4680 polymorphism of the COMT gene and the rs6265 polymorphism of the BDNF gene with the BIS and the Behavioral Activation System (BAS) in a population sample from Colombia. Methods: Genetic information was obtained by extracting DNA from blood samples of 80 participants and using Taqman probes designed for each polymorphism. In addition, participants completed a BIS/BAS scale in order to establish a neuropsychological classification. Results: The frequency of the Met allele of the BDNF gene was greater in the group with BIS sensitivity compared to the group with BAS sensitivity. On the contrary, the frequency of the Met allele of the COMT gen did not show a significant association with the BIS. Conclusions: The rs6265 polymorphism of BDNF gene is associated with the BIS which in turn constitutes a risk factor for anxiety and depression.

Brain-derived neurotrophic factor rs6265 (Val66Met) single nucleotide polymorphism as a master modifier of human pathophysiology.

Brain-derived neurotrophic factor is the most prevalent member of the nerve growth factor family. Since its discovery in 1978, this enigmatic molecule has spawned more than 27,000 publications, most of which are focused on neurological disorders. Brain-derived neurotrophic factor is indispensable during embryogenesis and postnatally for the normal development and function of both the central and peripheral nervous systems. It is becoming increasingly clear, however, that brain-derived neurotrophic factor likewise plays crucial roles in a variety of other biological functions independently of sympathetic or parasympathetic involvement. Brain-derived neurotrophic factor is also increasingly recognized as a sophisticated environmental sensor and master coordinator of whole organismal physiology. To that point, we recently found that a common nonsynonymous (Val66→Met) single nucleotide polymorphism in the brain-derived neurotrophic factor gene (rs6265) not only substantially alters basal cardiac transcriptomics in mice but subtly influences heart gene expression and function differentially in males and females. In addition to a short description of recent results from associative neuropsychiatric studies, this review provides an eclectic assortment of research reports that support a modulatory role for rs6265 including and beyond the central nervous system.

Associations of Brain-Derived Neurotropic Factor rs6265 Gene Polymorphism with Personality Dimensions among Athletes.

Brain-Derived Neurotropic Factor (BDNF) is one of the essential mediating factors of exercise-induced neuroplasticity, but the underlying molecular mechanisms of exercise-induced neuroplasticity are still largely unknown. Personality dimensions differentiate individuals and depend on genes and environmental factors. The dimensions of openness to experience, emotional stability, extraversion and conscientiousness have been reported to be positively related to performance; considering agreeableness, a negative relation with sports performance was emphasized. However, not enough effort has been put into investigating the relationship between genetic polymorphisms affecting psychological abilities and competitive power sports. The aim of this study was to investigate the association of the rs6265 polymorphism of BDNF with personality dimensions in martial arts athletes. The study was conducted among martial arts athletes. The study group included 258 volunteers (martial arts athletes (n = 106) and controls (n = 152). BDNF polymorphism testing was performed using the real-time PCR method; personality dimensions were assessed using standardized NEO-FFI questionnaires. All analyses were performed using STATISTICA 13. We observed that martial arts athletes' G/G genotypes compared to the control group G/G genotypes presented significantly higher severity of personality dimension "conscientiousness". In comparison with the controls, the case group subjects had significantly higher scores in the dimension extraversion (M 6.89 vs. M 6.43, p = 0.0405) and conscientiousness/scale (M 7.23 vs. M 5.89, p < 0.0001). The results of 2 × 3 factorial ANOVA noticed a statistically significant effect of combined factor BDNF rs6265 genotype of martial arts/control (F2,252 = 3.11, p = 0.0465, η2 = 0.024). Additionally, we observed that the results of 2 × 3 factorial ANOVA showed a statistically significant influence of combined factor BDNF rs6265 of genotype martial arts/ control (F2,252 = 6.16, p = 0.0024, η2 = 0.047). The combination of the analysis of personality dimensions with genetics­as in the case of the polymorphism of the BDNF gene related to neuroplasticity­indicates that neurobiology cannot be ignored in educating sports champions. We already know that this is related to genetics. However, little is still known about the influence of personality traits on sports performance. We observed that martial arts athletes' G/G genotypes, in comparison to the control group's G/G genotypes, presented significantly higher severity of personality dimension "conscientiousness". This is worthy of further analysis and probably longitudinal studies on a more numerous group of athletes.

New Frontiers in Neurodegeneration and Regeneration Associated with Brain-Derived Neurotrophic Factor and the rs6265 Single Nucleotide Polymorphism.

Brain-derived neurotrophic factor is an extensively studied neurotrophin implicated in the pathology of multiple neurodegenerative and psychiatric disorders including, but not limited to, Parkinson's disease, Alzheimer's disease, Huntington's disease, traumatic brain injury, major de-pressive disorder, and schizophrenia. Here we provide a brief summary of current knowledge on the role of BDNF and the common human single nucleotide polymorphism, rs6265, in driving the pathogenesis and rehabilitation in these disorders, as well as the status of BDNF-targeted therapies. A common trend has emerged correlating low BDNF levels, either detected within the central nervous system or peripherally, to disease states, suggesting that BDNF replacement therapies may hold clinical promise. In addition, we introduce evidence for a distinct role of the BDNF pro-peptide as a biologically active ligand and the need for continuing studies on its neurological function outside of that as a molecular chaperone. Finally, we highlight the latest research describing the role of rs6265 expression in mechanisms of neurodegeneration as well as paradoxical advances in the understanding of this genetic variant in neuroregeneration. All of this is discussed in the context of personalized medicine, acknowledging there is no "one size fits all" therapy for neurodegenerative or psychiatric disorders and that continued study of the multiple BDNF isoforms and genetic variants represents an avenue for discovery ripe with therapeutic potential.

BDNF rs6265 single-nucleotide polymorphism is involved in levodopa-induced dyskinesia in Parkinson's disease via its regulation of the cortical thickness of the left postcentral gyrus.

Background: Brain-derived neurotrophic factor (BDNF) gene rs6265 single-nucleotide polymorphism (SNP) is thought to be involved in neuroplasticity and influence the development of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). This study aimed to determine how the BDNF rs6265 SNP regulates cortical thickness and to investigate the association between BDNF and the pathological mechanisms of LID in PD. Methods: This cross-sectional study recruited 75 patients with PD, including 37 patients with LID and 38 patients without LID, and 33 healthy controls. All the participants underwent T1-weighted magnetic resonance imaging (MRI) scans, clinical evaluations, and BDNF rs6265 genotyping. Two-way factorial analysis of covariance (ANCOVA) was used to explore the primary effects of disease status, rs6265 genotype, and their interactions on cortical thickness. Associations between cortical thickness in the regions of the brain affected by disease status-genotype interactions and clinical symptoms were detected using Spearman's rank-order correlation. Receiver operating characteristic (ROC) curve analysis was used to test cortical thickness measurements as an indicator of LID. Results: The main effects of disease status were observed in the right pars orbitalis (F=4.229, P=0.017), medial orbitofrontal cortex (F=3.639, P=0.030), and left banks superior temporal sulcus (F=3.172, P=0.046). The left pars orbitalis (F=4.541, P=0.036) and lingual gyrus (F=4.307, P=0.041) were thicker in carriers of the CC genotype than in carriers of the TC/TT genotype. Interaction between disease status and genotype showed that in the LID group, carriers of the CC genotype had a thicker left postcentral gyrus (mean difference =0.103, 95% confidence interval, 0.036 to 0.107, Bonferroni-corrected P<0.005) than did carriers of the TC/TT genotype, whereas no difference was found in the non-LID and healthy control (HC) groups. In carriers of the CC genotype, the cortical thickness of the left postcentral gyrus could identify whether patients with PD had LID, with an area under the receiver operating curve (AUC) of 0.757 (P=0.033, optimal cut-off =2.102). The cortical thickness of the left postcentral gyrus was also positively correlated with the Unified Dyskinesia Rating Scale (UDysRS) score in the LID-CC subgroup (r=0.825, P=0.001). Conclusions: The BDNF rs6265 SNP might be associated with dyskinesia symptoms in patients with PD and LID through its regulation of cortical thickness in the left postcentral gyrus.

Association of serum BDNF level and Val66Met polymorphism with response to treatment in patients of major depressive disease: A step towards personalized therapy.

BACKGROUND: Major depressive disorder (MDD) is one of the most common psychiatric disorders and only less than 50% of MDD patients achieve remission after the first antidepressant trial. Hence, it is important to understand the factors associated with response to various antidepressant medications. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family. BDNF and Val66Met polymorphism in the BDNF gene has a role in MDD. This study aimed to determine the association of rs6265 polymorphism and serum BDNF level with response to treatment in MDD patients. METHODS: The study included 200 subjects, consisting of 100 MDD patients treated with oral antidepressants and 50 treated with ECT, and 50 healthy controls. Serum BDNF levels were estimated using ELISA and rs6265 polymorphism was genotyped using tetra-primer ARMS PCR. RESULTS: Val66Met polymorphism had an association with MDD, and in MDD patients with Met allele was associated with a better response to antidepressants. Serum BDNF level was significantly higher in MDD patients compared to healthy individuals. In MDD patients, lower serum BDNF level was associated with better ECT outcomes. CONCLUSIONS: Val66Met polymorphism in BDNF gene and serum BDNF level has the potential to be used as a biomarker for the prediction of response to oral antidepressants and ECT in MDD patients. The presence of the Met allele might be used to predict the chances of occurrence of MDD in the future. The results of our study might form a basis for the development of personalized treatment for MDD in the future.

CORRELATION BETWEEN RS6265 SNP IN BDNF AND THE CONTEXT OF DIABETES TYPE II INVOLVEMENT IN IRAQI PATIENTS.

OBJECTIVE: The aim: In this study, we looked into the possible link between the G196A polymorphism in the BDNF gene and DM in Iraqi patients. PATIENTS AND METHODS: Materials and methods: By using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach, 100 subjects were genotyped for the G196A SNP of the BDNF gene, 50 as DM and 50 as controls, age-sex and ethnically matched healthy controls. Analysis of covariance (ANCOVA) was used to assess the association of this polymorphism, and genotype frequencies were compared between patients and healthy controls. RESULTS: Results: Our result show that patient with the AG (Val-Met) genotype had a 40%of total DM patients than those and GG (Val-Val) genotypes. Therefore, we concluded that as a future aspect of the report the work can be further extended on proteomic level wherein the corresponding change occurred due to the mutation in the protein can be further detected at structural and functional level. CONCLUSION: Conclusions: conclusion of our result was any patient with covid-19 must need to follow up for at least 1 month after recovery to notified of the post-Covid symptoms especially the male gender.

The BDNF Val66Met Polymorphism (rs6265) Modulates Inflammation and Neurodegeneration in the Early Phases of Multiple Sclerosis.

The clinical course of multiple sclerosis (MS) is critically influenced by the interplay between inflammatory and neurodegenerative processes. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265), one of the most studied single-nucleotide polymorphisms (SNPs), influences brain functioning and neurodegenerative processes in healthy individuals and in several neuropsychiatric diseases. However, the role of this polymorphism in MS is still controversial. In 218 relapsing-remitting (RR)-MS patients, we explored, at the time of diagnosis, the associations between the Val66Met polymorphism, clinical characteristics, and the cerebrospinal fluid (CSF) levels of a large set of pro-inflammatory and anti-inflammatory molecules. In addition, associations between Val66Met and structural MRI measures were assessed. We identified an association between the presence of Met and a combination of cytokines, identified by principal component analysis (PCA), including the pro-inflammatory molecules MCP-1, IL-8, TNF, Eotaxin, and MIP-1b. No significant associations emerged with clinical characteristics. Analysis of MRI measures evidenced reduced cortical thickness at the time of diagnosis in patients with Val66Met. We report for the first time an association between the Val66Met polymorphism and central inflammation in MS patients at the time of diagnosis. The role of this polymorphism in both inflammatory and neurodegenerative processes may explain its complex influence on the MS course.

Interaction Effect between Physical Activity and the BDNF Val66Met Polymorphism on Depression in Women from the PISMA-ep Study.

The relationship between depression and the Val66Met polymorphism at the brain-derived neurotrophic factor gene (BDNF), has been largely studied. It has also been related to physical activity, although the results remain inconclusive. The aim of this study is to investigate the relationship between this polymorphism, depression and physical activity in a thoroughly characterised sample of community-based individuals from the PISMA-ep study. A total of 3123 participants from the PISMA-ep study were genotyped for the BDNF Val66Met polymorphism, of which 209 had depression. Our results are in line with previous studies reporting a protective effect of physical activity on depression, specifically in light intensity. Interestingly, we report a gene-environment interaction effect in which Met allele carriers of the BDNF Val66Met polymorphism who reported more hours of physical activity showed a decreased prevalence of depression. This effect was observed in the total sample (OR = 0.95, 95%CI = 0.90-0.99, p = 0.027) and was strengthened in women (OR = 0.93, 95%CI = 0.87-0.98, p = 0.019). These results highlight the potential role of physical activity as a promising therapeutic strategy for preventing and adjuvant treatment of depression and suggest molecular and genetic particularities of depression between sexes.

Association of BDNF gene missense polymorphism rs6265 (Val66Met) with three quantitative traits, namely, intelligence quotient, body mass index, and blood pressure: A genetic association analysis from North India.

Background: Brain-derived neurotrophic factor (BDNF), a neurotransmitter modulator, plays a significant role in neuronal survival and growth and participates in neuronal plasticity, thus being essential for learning, memory, and the development of cognition. Additionally, it is crucial for appetite, weight, and metabolic control and plays a pivotal role in the cardiovascular system. The Val66Met polymorphism (rs6265) of the BDNF gene causes a decrease in BDNF secretion and plays a role in impairments in cognition, energy homeostasis, and cardiovascular events. The present study aimed to evaluate the association of polymorphism (rs6265) of the BDNF gene with three quantitative traits simultaneously, namely, intelligence quotient (IQ), body mass index (BMI), and blood pressure (BP). Methods: Psychometric, morphometric, and physiometric data of the total participants (N = 246) were collected. WASI-IIINDIA was used to measure cognitive ability. Genotyping was carried out using allele-specific PCR for the rs6265 polymorphism (C196T), and genotypes were determined. Statistical analyses were performed at p < 0.05 significance level using MS-Excel and SigmaPlot. The odds ratio models with a 95% confidence interval were used to test the associations. The used models are co-dominant, recessive, dominant, over-dominant, and additive. Results: The allelic frequencies of alleles C and T were 72 and 28%, respectively. Under the dominant genetic model, a significant susceptible association of minor allele T was observed with a lower average verbal comprehensive index (OR = 2.216, p = 0.003, CI (95%) =1.33-3.69), a lower average performance reasoning index (OR = 2.634, p < 0.001, CI (95%) = 1.573-4.41), and a lower average full-scale IQ-4 (OR = 3.159, p < 0.001, CI (95%) = 1.873-5.328). Carriers of Met-alleles were found to have an increased body mass index (OR = 2.538, p < 0.001, CI (95%) = 1.507-4.275), decreased systolic blood pressure (OR = 2.051, p = 0.012, CI (95%) = 1.202-3.502), and decreased diastolic blood pressure (OR = 2.162, p = 0.006, CI (95%) = 1.278-3.657). Under the recessive genetic model, several folds decrease in IQ and BP and an increase in BMI with the presence of the T allele was also detected. Conclusion: This novel study may improve our understanding of genetic alterations to the traits and hence be helpful for clinicians and researchers to investigate the diagnostic and prognostic value of this neurotrophic factor.

Neurostructural correlates of BDNF rs6265 genotype in youth bipolar disorder.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) rs6265 single-nucleotide polymorphism has been associated with bipolar disorder (BD), and with brain structure among adults with BD. We set out to investigate the association of the BDNF rs6265 Met allele with neurostructural phenotypes in youth BD. METHODS: Caucasian youth (N = 99; 13-20 years; n = 56 BD, n = 43 age and sex-matched healthy controls) underwent 3-Tesla Magnetic Resonance Imaging and genotyping for BDNF rs6265. Region of interest (ROI) analyses of the ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), and hippocampus were complemented by vertex-wise analyses examining cortical thickness, surface area (SA) and volume. Multivariable models included the main effects of diagnosis and gene, and a diagnosis-by-genotype interaction term, controlling for age, sex, and intracranial volume. RESULTS: There were no significant gene main effects or diagnosis-by-gene interaction effects in ROI analyses. The vertex-wise analysis yielded a significant gene main effect whereby Met allele carriers had greater middle temporal gyrus SA (p = 0.001) and supramarginal gyrus volume (p = 0.03) than Val/Val individuals. Significant interaction effects were found on lateral occipital lobe SA (p = 0.03), whereby the Met allele was associated with increased SA in BD only. Interaction effects were also found on postcentral gyrus SA (p = 0.049) and supramarginal gyrus SA (p = 0.04), with smaller SA in BD Met carriers versus healthy control Met carriers. CONCLUSION: These findings suggest that BDNF rs6265 is differentially associated with regional SA in youth BD. Further investigation is warranted to evaluate whether BDNF protein levels mediate the observed effects, and to evaluate rs6265-related developmental changes.

BDNF rs6265 Genotype Influences Outcomes of Pharmacotherapy and Subthalamic Nucleus Deep Brain Stimulation in Early-Stage Parkinson's Disease.

INTRODUCTION: The efficacy of pharmacotherapy and deep brain stimulation of the subthalamic nucleus in treating Parkinson's disease motor symptoms is highly variable and may be influenced by patient genotype. The relatively common (prevalence about one in three) and protein-altering rs6265 single nucleotide polymorphism (C > T) in the gene BDNF has been associated with different clinical outcomes with levodopa. OBJECTIVE: We sought to replicate this reported association in early-stage Parkinson's disease subjects and to examine whether a difference in clinical outcomes was present with subthalamic nucleus deep brain stimulation. MATERIALS AND METHODS: Fifteen deep brain stimulation and 13 medical therapy subjects were followed for 24 months as part of the Vanderbilt DBS in Early Stage PD clinical trial (NCT00282152, FDA IDE #G050016). Primary outcome measures were the Unified Parkinson's Disease Rating Scale (UPDRS) and Parkinson's Disease Questionnaire-39. RESULTS: Outcomes with drug therapy in subjects carrying the rs6265 T allele were significantly worse following 12 months of treatment compared to C/C subjects (UPDRS: +20 points, p = 0.019; PDQ-39: +16 points, p = 0.018). In contrast, rs6265 genotype had no effect on overall motor response to subthalamic nucleus deep brain stimulation at any time point; further, rs6265 C/C subjects treated with stimulation were associated with worse UPDRS part II scores at 24 months compared to medical therapy. CONCLUSIONS: Genotyping for the rs6265 polymorphism may be useful for predicting long-term response to drug therapy and counseling Parkinson's disease patients regarding whether to consider earlier subthalamic nucleus deep brain stimulation. Validation in a larger cohort of early-stage Parkinson's disease subjects is warranted.

The connection between rs6265 polymorphism in the BDNF gene and successful mastering of the video-oculographic interface.

A video-oculographic interface is a system for controlling objects using eye movements. The video-oculographic interface differs from other brain-computer interfaces regarding its improved accuracy, simplicity, and ergonomics. Despite these advantages, all users are not equally successful in mastering these various devices. It has been suggested that the genetic characteristics of the operators may determine the efficiency of video-oculographic interface mastery. We recruited healthy users with rs6313, rs2030324, rs429358, rs10119, rs457062, rs4290270, and rs6265 polymorphisms and analyzed the relationships between these polymorphisms and values of success in video-oculographic interface mastery. We found that carriers of the G/G genotype of the rs6265 polymorphism (BDNF gene) demonstrated the best results in video-oculographic interface mastery. In contrast, carriers of the A/A genotype were characterized by large standard deviations in the average amplitude of eye movement and the range of eye movement negatively correlated with goal achievement. This can be explained through the fact that carriers of the A/A genotype demonstrate lower synaptic plasticity due to reduced expression of BDNF when compared to carriers of the G/G genotype. These results expand our understanding of the genetic predictors of successful video-oculographic interface management, which will help to optimize device management training for equipment operators and people with disabilities.

Sex-Based Differences in Cardiac Gene Expression and Function in BDNF Val66Met Mice.

Brain-derived neurotrophic factor (BDNF) is a pleiotropic neuronal growth and survival factor that is indispensable in the brain, as well as in multiple other tissues and organs, including the cardiovascular system. In approximately 30% of the general population, BDNF harbors a nonsynonymous single nucleotide polymorphism that may be associated with cardiometabolic disorders, coronary artery disease, and Duchenne muscular dystrophy cardiomyopathy. We recently showed that transgenic mice with the human BDNF rs6265 polymorphism (Val66Met) exhibit altered cardiac function, and that cardiomyocytes isolated from these mice are also less contractile. To identify the underlying mechanisms involved, we compared cardiac function by echocardiography and performed deep sequencing of RNA extracted from whole hearts of all three genotypes (Val/Val, Val/Met, and Met/Met) of both male and female Val66Met mice. We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including increased systolic (26.8%, p = 0.047) and diastolic diameters (14.9%, p = 0.022), increased systolic (57.9%, p = 0.039) and diastolic volumes (32.7%, p = 0.026), and increased stroke volume (25.9%, p = 0.033), with preserved ejection fraction and fractional shortening. Both males and females exhibited lower heart rates, but this change was more pronounced in female mice than in males. Consistent with phenotypic observations, the gene encoding SERCA2 (Atp2a2) was reduced in homozygous Met/Met mice but more profoundly in females compared to males. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. Homozygous male mice on the other hand exhibited an inflammatory profile characterized by interferon-γ (IFN-γ)-mediated Th1 immune responses. These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, including female-specific alterations of cardiac-specific transcripts and male-specific activation of inflammatory targets.

The impact of CPT1B rs470117, LEPR rs1137101 and BDNF rs6265 polymorphisms on the risk of developing obesity in an Italian population.

OBJECTIVE: This study aimed to analyze 11 single nucleotide polymorphisms (SNPs) belonging to 9 genes involved in metabolic pathways (BDNF rs6265; PNPLA3 rs2294918 and rs2076212; CIDEA rs11545881; NTRK2 rs2289658; ALOX12 rs1126667; ALOX12B rs2304908; LEPR rs1137101; CPT1B rs470117 and rs8142477; rs2305507 CPT1A) in obese patients and controls. METHODS: Polymorphisms were analyzed in 300 severe obese patients undergoing bariatric surgery (body mass index >30 kg/m2) and 404 control subjects in order to evaluate their association with obesity and clinical variables. RESULTS: Our findings showed significant differences for the allelic distributions of CPT1B rs470117 and LEPR rs11371010 in obese subjects compared to controls. The BDNF rs6265 correlates with obesity only when associated with the other two SNPs. In particular, for CPT1B rs470117 and LEPR rs1137101, the rare allele was associated with a reduced risk of developing the obese phenotype, whereas the simultaneous presence of the common C allele for rs470117 and A allele for rs1137101 was more frequent in obese patients (p = 0.002, OR = 1.417). A significant association between CPT1B rs470117 and steatosis was found. Moreover, we observed that by associating the rare allele T of the BDNF rs6265 with the most common alleles of the SNPs CPT1B rs470117 and LEPR rs1137101, the combination of T-C-A alleles was associated with a higher risk of developing an obese phenotype (p = 0.001, OR = 1.6679). CONCLUSIONS: Our results suggest that SNPs CPT1B rs470117 and LEPR rs1137101 taken individually and in association with BDNF rs6265 may be involved in an increased risk of developing obese phenotype in an Italian cohort.