Brain-derived Neurotrophic Factor G196A Research Articles

Associations of Plasma BDNF and BDNF Gene Polymorphism with Cardiometabolic Parameters in Thai Children: A Pilot Study.

Childhood obesity is an important public health crisis worldwide. The brain-derived neurotrophic factor (BDNF) has been demonstrated to play a role in controlling energy homeostasis and cardiovascular regulation. To examine brain-derived neurotrophic factor (BDNF) levels and anthropometric-cardiometabolic and hematological parameters in obese and nonobese children and to determine whether two BDNF gene polymorphisms (G196A and C270T) are linked to BDNF levels, obesity, and anthropometric-cardiometabolic and hematological parameters among Thai children. This case-control study included an analysis of 469 Thai children: 279 healthy nonobese and 190 obese children. Anthropometric-cardiometabolic and hematological variables and BDNF levels were measured. Genotyping of BDNF G196A and C270T was performed using the polymerase chain reaction-restriction fragment length polymorphism technique. Children in the obese group had significantly higher white blood cell counts and some cardiometabolic parameters. Although the difference in BDNF level between the nonobese and obese groups was not significant, BDNF level was significantly positively correlated with hematological and cardiometabolic parameters, including blood pressure, triglycerides, and triglycerides and the glucose index. The BDNF G196A polymorphism in children was only associated with decreased systolic blood pressure (p < 0.05), while the BDNF C270T polymorphism was found not to be related to BDNF levels, obesity, or other parameters after adjusting for potential covariates. These findings in Thai children suggest that obesity is associated with increased cardiometabolic risk factors, but not with BDNF levels or the two BDNF polymorphisms studied, while the BDNF G196A polymorphism is a beneficial marker for controlling blood pressure among Thai children.

Brain-derived neurotrophic factor G196A (rs6265) gene polymorphism increases Turner syndrome susceptibility

ABSTRACT Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family. It plays a significant role in the regulation of brain metabolic activity, modification of synaptic efficacy, and enhances neuronal survival. A common naturally occurring allelic variation, i.e. G196A (Val66 Met, rs6265) of the BDNF gene is implicated in neuroplasticity. This study analyzes its expression levels and determines the frequency of BDNF G196A gene polymorphism in women with Turner syndrome (TS) compared to the controls. This case–control study comprised 14 TS patients and 8 healthy individuals. The expression levels of BDNF gene in TS patients were checked by qPCR. For BDNF gene, a dynamic expression range along with the presence of G196A polymorphism was found across all TS patients. The effects of Val66 Met mutation on BDNF protein structure and function were studied by molecular dynamics simulations of wild and mutant (Val66 Met) forms. The analysis of different trajectories generated by simulation showed that there was a significant change in the protein structure due to Val66 Met polymorphism, which might lead to functional impairment. This is first time we are reporting the association of BDNF G196A gene polymorphism with TS risk. Our study suggests that in turner patients, BDNF G196A polymorphism may be an important genetic factor predisposing to neuroplasticity risk and can be exploited as diagnostic/prognostic marker for TS. Further study on a large number of TS samples will prove this point beyond doubts or otherwise enriching the much desired repertoire of personalized medicine.

Association between BDNF G196A (Val66Met) polymorphism and cognitive impairment in patients with Parkinson's disease: a meta-analysis.

Brain-derived neurotrophic factor (BDNF) is widely expressed in the central nervous system and prolongs the survival of dopaminergic neurons in the substantia nigra. Several studies have recently investigated the association between BDNF G196A (Val66Met), a single nucleotide polymorphism influencing cognitive processes, and cognitive impairment in Parkinson's disease (PD), but with contradictory findings. Thus, this meta-analysis was performed to clarify the possible association. Relevant studies were identified by a systematic search of PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases. The strength of the association was evaluated using crude odds ratios and 95% confidence interval. Finally, six studies involving 532 cases and 802 controls were included. Our analyses suggested the G196A (Val66Met) polymorphism was significantly associated with cognitive impairment in PD, especially in Caucasian populations. In conclusion, BDNF G196A (Val66Met) is confirmed to be a risk factor for cognitive impairment in PD.

Association of BDNF G196A Gene Polymorphism with Ischemic Stroke Occurrence and its 6-Month Outcome in an Iranian Population

Background: Genetic factors like the allele for Brain-Derived Neurotrophic Factor (BDNF) are associated with the outcome of ischemic stroke most likely through affecting neural differentiation and synaptic plasticity. Studies of the association of BDNF G196A gene polymorphism and long-term ischemic stroke outcome in various populations have not been concordant.Objective: In this research, the association of BDNF G196A gene polymorphism and ischemic stroke occurrence were studied in a northern Iranian population with a glance to its 6-month outcome.Methods: The genetic variant of BDNF G196A was examined in Ischemic Stroke (IS) patients (n = 206) and control group (n = 200). In IS individuals, outcome variables such as stroke severity, functional disability, and cognitive impairment were examined, respectively, by NIHSS, Barthel Index, and MoCA in an average of 202 days after the stroke occurrence.Results: The frequency of risk allele G was 12.1% in IS patients and 5.5% in healthy individuals; and the difference was statistically significant (p < 0.0001). The frequency of risk genotype GG, heterozygote and homozygote were 0% and 1%, 24%.3% and 9%, 75.7% and 90%, respectively, for IS and control groups (p < 0.05). After controlling the phenotype confounding factors, logistic regression analysis showed that there was a borderline significant relationship between genotype BDNF GA + GG and IS occurrence (AOR = 1.997,95% CI: 0.252–1.010, p = 0.051). There was no significant difference between the various genotypic groups regarding the severity of the stroke and functional disability. Yet, G allele carriers had more cognitive impairment after IS (p = 0.002).Conclusion: For the first time in an Iranian population, it was demonstrated that BDNF G196A variant plays a major role in stroke occurrence and consequences. It is suggested that, after IS, G allele carriers should have precedence for medicinal and rehabilitation interventions, in order to reduce their cognitive deficiency.

The serum concentrations of brain derived neurotrophic factor and its G196A polymorphism in amphetamine induced-psychosis inpatients

Objective To investigate the relationship between the serum concentrations of brain derived neurotrophic factor (BDNF) and its G196A polymorphism in the amphetamine induced-psychosis inpatients. Methods The cross-sectional study included 233 amphetamine abuses and 110 healthy participants who served as controls. The serum concentration of BDNF was measured by sandwich ELISA, and the genotype of BDNF G196A polymorphism was determined used polymerase chain reaction (PCR) techniques. The data were analyzed using SPSS 12.0 statistics software. Results The serum concentration of BDNF in case group((205.81±75.36) pg/ml) were significantly higher than that in control group((95.04±31.63) pg/ml; t=15.02, P 0.05). The BDNF serum concentration showed no significant difference in the genotype distributions and allele frequencies (P>0.05). The genotype distributions and allele frequencies of BDNF G196A showed no significant difference among three groups(P>0.05). Conclusion The BDNF serum concentration is correlated with methamphetamine abuse, while the BDNF G196A gene polymorphism may not be associated. Key words: Methamphetamine abuse; Brain-derived neurotrophic factor; Gene polymorphism

BDNF G196A (Val66Met) polymorphism associated with cognitive impairment in Parkinson's disease

Brain-derived neurotrophic factor (BDNF) is a neurotrophin widely expressed in the mammalian brain, regulating neuronal survival and known to influence dopaminergic neurons and cognitive processes. The present study investigated the BDNF Val66Met polymorphism associations with PD risk, and cognitive impairment in PD. A total of 486 study subjects (244 PD and 242 age and sex matched controls) were included in the study. UPDRS score, Hoehn–Yahr staging and the Schwab–England scale were used to assess motor abilities and activity during daily life. The patients were classified into groups with dementia (PDD, n=69) and without it (nPDD, n=166) on the basis of neuropsychological assessment. The most common functional polymorphism in BDNF Val66Met (rs6265, G196A) gene was determined using TaqMan real-time PCR assay. Frequencies of evaluated BDNF alleles and genotypes were similar in PD and the controls. The mean age of disease onset among BDNF Met/Met carriers was later (65.00±6.13) in comparison to Val/Val (57.45±10.68) and Val/Met (56.33±10.91) subjects (p=0.077). The studied BDNF polymorphism was not associated with cognitive status in PD patients. However, patients with Met/Met alleles demonstrated better delayed recall of information than patients with Val/Val alleles. The results of multivariate logistic regression analysis revealed age (p=0.0003) and the disease stage (p=0.002) as independent risk factors predisposing to PD dementia.

Analysis of genetic polymorphisms of brain-derived neurotrophic factor and methylenetetrahydrofolate reductase in depressed patients in a Slovak (Caucasian) population

Major depressive disorder (MDD) is a complex neuropsychiatric disorder where both gene-gene and gene-environment interactions play an important role, but the clues are still not fully understood. One carbon metabolism in the CNS plays a critical role in the synthesis and release of neurotransmitters which are relevant to depressive disorder. We studied genetic polymorphisms of the brain derived neurotrophic factor (BDNF) and the methylenetetrahydrofolate reductase (MTHFR) in association with major depressive disorder. We genotyped the BDNF G196A, the MTHFR C677T, and A1298C polymorphisms in 134 patients diagnosed with major depression and 143 control subjects in Slovak (Caucasian) cohort of patients and probands. We found no significant association of either the BDNF G196A or MTHFR C677T polymorphisms with major depressive disorder neither in female nor male group of patients. However, the MTHFR A1298C genotype distribution was 36.6% (for AA genotype), 48.5% (AC) and 14.9% (CC) for the depressed patients, and 48.9% (AA), 42.7% (AC) and 8.4% (CC), respectively, for the control subjects. Patients with MDD had a higher prevalence of the CC genotype (OR = 2.38; 95% CI = 1.07-5.32; p = 0.032) and the AC + CC genotype (OR = 1.67; 95% CI = 1.03-2.69; p = 0.037) in comparison with the control subjects. This study shows that CC genotype of the MTHFR A1298C is associated with higher risk of MDD in Slovak population.

BDNF Val66Met polymorphism is associated with cognitive impairment in Italian patients with Parkinson’s disease

A possible association between Parkinson's disease (PD) and the polymorphism of Brain Derived Neurotrophic Factor (BDNF) G196A (Val66Met) has been suggested by different studies that nevertheless yielded-contrasting result. The purpose of this study was to analyze such possible association in a cohort of Italian PD patients. The BDNF polymorphisms were analyzed in 294 Italian patients with PD; results were compared to those obtained in 233 age- and sex-matched healthy controls (HC) enrolled from two tertiary centres in Italy. Polymorphisms were determined by Restriction Fragment Length Polymorphism (RFLP) analysis; correlations between BDNF G196A polymorphism, and cognitive function were established by sub analyzing the results upon dividing PD patients based on their Mini Mental State Examination (MMSE) score. Univariate analysis showed a highly significant correlation between the BDNF(AA) genotype and a MMSE score < or =24. Hence, the distribution of this genotype in PD individuals with a MMSE score < or =24 was significantly increased compared to PD patients with an MMSE score >24 and HC (P < 0.001 in both cases). Multivariate analyses showed that BDNF (AA) genotype was associated to a sixfold risk of cognitive impairment. The BDNF(AA) homozygote genotype is over-represented in PD patients compared with normal individuals; this genotype was significantly correlated to cognitive impairment, age and disease severity. These results, although preliminary, could be important in establishing novel diagnostic and therapeutic approaches to PD.

Brain‐derived neurotrophic factor gene polymorphisms and serum levels in Chinese atopic dermatitis patients

Brain-derived neurotrophic factor (BDNF) plays an important role in the pathogenesis of atopic dermatitis (AD). Whether BDNF gene polymorphisms are associated with Chinese AD remains totally unknown. The aim is to determine if BDNF gene C270T and G196A polymorphisms are associated with Chinese AD, and analyse the clinical relevance of BDNF gene polymorphisms and BDNF serum levels. Methods We conducted a case-control association analysis (160 patients and 169 controls) in Northern Chinese subjects. Genotyping was performed by restriction fragment length polymorphism, and serum levels of BDNF were measured using enzyme-linked immunosorbent assay. For C270T, there were significant differences in C/T genotype distribution (P = 0.003) and T allele frequencies (P = 0.004) between AD patients and controls in the whole dataset. Higher C/T genotype frequencies were found in male AD (10.6% vs. 1.1%, P = 0.018) and in intrinsic AD (IAD; 15.79% vs. 2.91%, P = 0.008). No association between G196A polymorphism and AD was observed in the whole cohort, while A allele was much more frequent in AD patients with atopy in first-degree relatives (65.8% vs. 34.2%, P = 0.038). Serum BDNF levels were correlated with IAD severity as measured by Scoring Atopic Dermatitis index (r = 0.576, P < 0.001). T allele in C270T may be a risk factor for AD, especially in IAD and male AD. A allele in G196A may be a risk factor in AD patients with atopy in first-degree relatives. Serum BDNF levels were correlated with the severity of IAD.

Association analysis of serotonin receptor 1B (HTR1B) and brain-derived neurotrophic factor gene polymorphisms in borderline personality disorder

The purpose of this study was to test for association between Borderline personality disorder (BPD) and variants of the HTR1B and the brain-derived neurotrophic factor (BDNF) gene. We genotyped four HTR1B and the functional BDNF G196A marker in 161 Caucasian BPD patients and 156 healthy controls. There were no significant differences between groups in genotype or haplotype distribution of HTR1B markers or in genotype distribution of the BDNF marker. Logistic regression analyses revealed an over-representation of the BDNF 196A allele in HTR1B A-161 allele carrying BPD patients.

Association between brain‐derived neurotrophic factor gene and a severe form of bipolar disorder, but no interaction with the serotonin transporter gene

Recent data suggest that brain-derived neurotrophic factor (BDNF) and the serotonergic system are involved and interact in major depressive disorder and suicidal behavior (SB). Several family and population-based studies have reported associations between the BDNF gene and serotonin-related genes, specifically the serotonin transporter (5HTT) gene, with bipolar disorder (BD) and SB. However, despite the fact that gene-by-gene interaction between BDNF and 5HTT has been demonstrated in monoamine deficiencies in animals, this kind of interaction has never been tested in humans. Our hypothesis is that some BDNF and 5HTT polymorphisms might confer increased risk for BD and SB and that both genes may interact with each other. To test this hypothesis, we genotyped the most common BDNF polymorphisms, G196A (Val66Met), A-633T and BDNF-LCPR, as well as 5HTT (5HTT-LPR), in 447 BD patients and 370 controls. We replicated the association previously reported between BDNF G196A (Val66Met) polymorphism and BD. We also observed a correlation between the number of G196 alleles and short alleles of 5HTT-LPR and the severity of SB in BD. However, we found no significant interaction between these two markers. These results suggest that BDNF G196A as well as 5HTT-LPR polymorphisms confer risk for SB in BD, but we did not observe any evidence for an interaction between them.

Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

Decreased levels of brain-derived neurotrophic factor (BDNF) have been implicated in the pathogenesis of Alzheimer's disease and depression. These disorders are associated with type 2 diabetes, and animal models suggest that BDNF plays a role in insulin resistance. We therefore explored whether BDNF plays a role in human glucose metabolism. We included (Study 1) 233 humans divided into four groups depending on presence or absence of type 2 diabetes and presence or absence of obesity; and (Study 2) seven healthy volunteers who underwent both a hyperglycaemic and a hyperinsulinaemic-euglycaemic clamp. Plasma levels of BDNF in Study 1 were decreased in humans with type 2 diabetes independently of obesity. Plasma BDNF was inversely associated with fasting plasma glucose, but not with insulin. No association was found between the BDNF G196A (Val66Met) polymorphism and diabetes or obesity. In Study 2 an output of BDNF from the human brain was detected at basal conditions. This output was inhibited when blood glucose levels were elevated. In contrast, when plasma insulin was increased while maintaining normal blood glucose, the cerebral output of BDNF was not inhibited, indicating that high levels of glucose, but not insulin, inhibit the output of BDNF from the human brain. Low levels of BDNF accompany impaired glucose metabolism. Decreased BDNF may be a pathogenetic factor involved not only in dementia and depression, but also in type 2 diabetes, potentially explaining the clustering of these conditions in epidemiological studies.

The G196A polymorphism of the brain-derived neurotrophic factor gene and the antidepressant effect of milnacipran and fluvoxamine

Prediction of the response to different classes of antidepressants has been an important matter of concern in the field of psychopharmacology. The purpose of the present study was to investigate whether the G196A polymorphism of the brain-derived neurotrophic factor (BDNF) gene is associated with the antidepressant effect of milnacipran, a serotonin norepinephrine reuptake inhibitor, and fluvoxamine, a selective serotonin reuptake inhibitor. The subjects of our previous study of milnacipran (n = 80) and fluvoxamine (n = 54) were included in the present study. Severity of depression was assessed with the Montgomery Asberg depression rating scale (MADRS). Assessments were carried out at baseline and at 1, 2, 4 and 6 weeks of treatment. Polymerase chain reaction was used to determine allelic variants. In all subjects receiving milnacipran or fluvoxamine, the G/A genotype of the BDNF G196A polymorphism was associated with a significantly better therapeutic effect in the MADRS scores during this study. When milnacipran and fluvoxamine-treated subjects were analysed independently, the G/A genotype group showed greater reduction of MADRS scores than other genotype groups, irrespective of which antidepressant was administered. These results suggest that the BDNF G196A polymorphism in part determines the antidepressant effect of both milnacipran and fluvoxamine.

An association study of the brain-derived neurotrophic factor Val66Met polymorphism and amphetamine response.

Although genetic factors are known to be important in addiction, no candidate genes have yet been consistently linked to drug use or abuse. Brain-derived neurotrophic factor (BDNF), which has been implicated in the behavioral response to psychomotor stimulants and potentiates neurotransmitters that are strongly linked to addiction, is a logical candidate gene to study. Using a drug challenge approach, we tested for association between BDNF G196A (val66met) genotype and subjective responses to amphetamine (AMPH). Healthy volunteers participated in a double blind, crossover design in which they received placebo, 10 mg, and 20 mg oral d-amphetamine in random order. Subjective and physical responses to ingestion of AMPH were measured at 30-min intervals after drug ingestion. Each subject was genotyped for the BDNF G196A polymorphism and grouped and analyzed accordingly. The effects of AMPH on ratings of arousal, energy, and heart rate were compared in subjects with the val/val genotype (N = 67) and the subjects with either the val/met or met/met genotypes (N = 32). AMPH produced less pronounced self-ratings of arousal and energy, yet higher increases in heart rate, in the val/met and met/met compared to the val/val group. These results suggest that BDNF is related to the subjective and physical response to low doses of AMPH.

BDNF genetic variants are associated with onset age of familial Parkinson disease: Gene PD Study

Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.

Lack of association between two polymorphisms of brain-derived neurotrophic factor and response to typical neuroleptics

Several studies have connected brain-derived neurotrophic factor (BDNF) with treatment response to neuroleptics. In recent studies, the BDNF expression was reduced by typical neuroleptics. We conducted a retrospective study on 94 patients with schizophrenia and 98 controls. The BDNF G196A and C270T polymorphisms are not associated with treatment response to typical neuroleptics or with age at first hospitalization. Moreover, these polymorphisms of the BDNF gene are not associated with the risk of schizophrenia.