Brain-derived Neurotrophic Factor Polymorphism Research Articles

Brain-derived Neurotrophic Factors Val66Met and C270T Polymorphisms Influence Citalopram/Escitalopram Response in Chinese Patients with Major Depressive Disorder

The aim of this study was to investigate the association between two brain-derived neurotrophic factor polymorphisms (Val66Met and C270T) and response to citalopram/escitalopram treatment. Chinese patients who met diagnostic and Statistical Manual of Mental Disorders criteria for major depressive disorder (n=180) were prescribed citalopram/escitalopram for 6 weeks. Depression severity was evaluated using the 17-item Hamilton rating scale for depression at baseline and week 2, 4, and 6 of treatment. The expression quantitative trait loci analysis was performed to investigate the functional effect of Val66Met and C270T on brain-derived neurotrophic factor expression in the brain and blood. A significant difference was found in genotype (χ2=6.979, p=0.031, correction p=0.062) but not allele (p>0.05) frequencies of Val66Met between responders and non-responders. Homozygous GG showed a higher response than other two genotypes (χ2=5.218, p=0.022, correction p=0.044). In addition, the C allele and CC genotype of C270T were significantly related to higher remission over 6 weeks among females (C/T, p=0.027, correction p=0.054; CC/TT, p=0.023, correction p=0.046) and first-episode major depressive disorder patients (C/T, p=0.023, correction p=0.046; CC/TT, χ2= 6.870, p=0.009, correction p=0.018). Further expression quantitative trait loci analysis showed that Val66Met and C270T have functional effect on brain-derived neurotrophic factor expression in the brain. Brain-derived neurotrophic factor Val66Met and C270T polymorphisms were associated with therapeutic response to citalopram/escitalopram in Chinese major depressive disorder patients.

The Role of Val66Met Single Nucleotide Polymorphism in Brain-Derived Neurotropic Factor Gene in Prediction of Adverse Outcomes After ST-segment Elevation Myocardial Infarction

Background: The single nucleotide polymorphism of Val66Metgen of the brain-derived neurotrophic factor (BDNF) gene is a possible candidate that is associated with the development of psychopathology and combines it with cardiovascular events. The purpose of this study was to research the possible associations of single-nucleotide polymorphism of Val66Met BDNF gene with the occurrence of endpoints after 6 months of follow-up after ST-segment elevation myocardial infarction (STEMI). Materials and Methods: 256 acute STEMI patients after successful primary percutaneous coronary intervention (PCI) were enrolled in the study. Thrombolysis in myocardial infarction III blood flow restoring through culprit artery was determined. The study of single-nucleotide polymorphism of Val66Met gene BDNF (rs6265) was performed by real-time polymerase chain reaction. The emotional state of the patients and its relationship with stress were assessed with the questionnaire “Depression, Anxiety, and Stress-21”. Results: The frequency of genotypes Val66Met gene for BDNF in STEMI patients (n = 256) was the following: 66ValVal = 74.2% (n = 190), 66ValMet + 66MetMet - 25.8% (n = 66). The 66ValMet + 66MetMet polymorphism in the BDNF gene, stress, and anxiety on 10–14 days before the event, as well as reduced left ventricular ejection fraction, were independently associated with combined 6 months' clinical endpoint after STEMI. Conclusion: The Val66Met polymorphism in BDNF gene was found as an independent predictor for combined 6-month clinical endpoints after acute STEMI-treated primary PCI.

Genes of neurotrophic factors and responsiveness to antidepressive psychopharmacotherapy in patients with depressive disorders

Major depressive disorder (MDD) is a clinically and biologically heterogeneous disorder with a heavy personal and socio-economic burden [1]. The neurotrophic theory of the development of depression most fully explains the morphological changes that occur in the brain of patients [2,3]. Among the various neurotrophic factors brain-derived neurotrophic factor (BDNF) and prolactin play an important role in pathogenesis of depression [4]. Objective of the study was to investigate the association of genes polymorphisms of BDNF and prolactin with responsiveness to therapy in patients with MDD. Methods The study group included 185 MDD patients (F32,F33,ICD-10) and 134 healthy persons. Severity of depressive symptoms on the baseline and on the 14th and 28th day of therapy was assessed using Hamilton Depression Scale (HDRS-17) and Clinical Global Impression – Severity scale (CGI-S). Antidepressive therapy response on the 14th and 28th day of therapy was evaluated using Clinical Global Impression – Improvement scale (CGI-I). Genotyping was carried out on polymorphic variants of BDNF genes (rs6265, rs7124442, rs11030104) and PRL gene (rs1341239). The SPSS software was used for statistical analysis. The Hardy-Weinberg equilibrium (HWE) of genotypic frequencies was tested by the chi-square test. Results The study found no deviation of genotype frequencies from HWE (р > 0.05), except for the SNP rs11030104 in the group of patients (χ2 = 37.540; p = 0.001). Important differences in frequency of genotypes and alleles of SNPs rs11030104 of BDNF and rs1341239 of PRL genes between patients and healthy persons at entry have been found. The final multivariate binary logistic regression analysis shows that the A/A genotype of SNP rs11030104 has a more than 6 times higher risk of developing depression than G/G or G/A genotype (p = 0.009). Allele G of SNP rs1341239 gene was more common in patients (63%) compared to control (59%) (p <0.001). We studied the association between the scores on the HDRS-17, CGI-S and CGI-I scales and gene polymorphisms. A statistically significant reduction in scores on all scales during therapy was observed (p <0.01). A decreased scores on the HDRS-17 is associated with G/G genotype of SNP rs6265 (p = 0.049), C/C genotype of SNP rs7124442 (р = 0.009) and A/A genotype of SNP rs11030104 (p = 0.07), patients with these genotypes are characterized by mild depressive disorder on the 14th day of therapy. We showed a relationship between the carriage of the C allele of SNP rs7124442 (p = 0.014) and the G/G genotype of SNP rs6265 (p = 0.078) and a reduced CGI-S score indicating a good response to therapy in this patients. There was a correlation between the presence of the T allele of SNP rs1341239 and the absence of remission according to the CGI-S scale (p = 0.004) and the worst response to antidepressant therapy. Conclusions Our results suggest that SNPs rs11030104 of BDNF gene and rs1341239 of PRL gene are associated with higher risk of developing depression, SNPs rs6265 and rs7124442 of BDNF gene are probably related to the clinical characteristics of the disorder and the response to pharmacotherapy. Disclosure statement: This study was supported by the Russian Foundation Basic Research, grant No. 17-29-02205 “Development of a molecular-genetic panel of depressive disorders based on polymorphisms of the genes of neuronal kinases, neurotrophic proteins and genes of the serotonergic system”

A gene-based analysis of variants in the Brain-derived Neurotrophic Factor gene with psychological distress in a Taiwanese population

Background: Brain-derived neurotrophic factor (BDNF), the most abundant and widely expressed neurotrophin in the brain, is believed to play an important role in depression and anxiety. In this study, we hypothesized that single-nucleotide polymorphisms (SNPs) within the BDNF gene should be linked with depression and anxiety through complex interactions in the general population. Methods: We analyzed 7,098 Taiwanese participants from the Taiwan Biobank. Measures of anxiety and depression were evaluated using the Patient Health Questionnaire-4 (PHQ-4). We used 43 BDNF polymorphisms in the genetic analysis. Results: We found a nominal association between nine BDNF genetic variants and depression state, after having adjusted for the factors of age and gender. Furthermore, three BDNF SNPs showed evidence of nominal association with PHQ-4 scores. In addition, an interaction significantly existed between the BDNF rs73430670 and BDNF rs4923461 in influencing depression state (p

A gene–gene interaction between the vascular endothelial growth factor a and brain-derived neurotrophic factor genes is associated with psychological distress in the Taiwanese population

Background: Vascular endothelial growth factor A (VEGFA) and brain-derived neurotrophic factor (BDNF), the most abundant and widely expressed neurotrophic factors in the brain, are believed to play an important role in depression and anxiety. In this study, we hypothesized that single-nucleotide polymorphisms (SNPs) within the VEGFA and BDNF genes would be linked with psychological distress through complex interactions in the general population. Methods: We analyzed 7,098 Taiwanese subjects from the Taiwan Biobank. Measures of anxiety and depression were evaluated using the Patient Health Questionnaire-4 (PHQ-4). Totally, 15 VEGFA and 43 BDNF polymorphisms were used in the genetic analysis. Results: In our analysis, an interaction was found between the VEGFA rs10434 and BDNF rs12418745 in significantly influencing depression state (p

Memory Impairment and Plasma BDNF Correlates of the BDNF Val66Met Polymorphism in Patients With Bipolar II Disorder

Studies suggest that a functional polymorphism of brain-derived neurotrophic factor (BDNF), polymorphism BDNF Val66Met affects cognitive functions, however, the effect is unclear in bipolar II (BD-II) disorder. We used the Wechsler Memory Scale-third edition (WMS-III), the presence of the BDNF Val66Met polymorphism, and plasma concentrations of BDNF to investigate the association between memory impairment and BDNF in BD-II disorder. We assessed the memory functions of 228 BD-II patients and 135 healthy controls (HCs). BD-II patients had significantly lower scores on five of the eight WMS-III subscales. In addition to education, the BDNF polymorphism were associated with the following subscales of WMS-III, auditory delayed memory, auditory delayed recognition memory and general memory scores in BD-II patients, but not in HC. Moreover, BD-II patients with the Val-homozygote scored significantly higher on the visual immediate memory subscale than did those with the Met/Met and Val/Met polymorphisms. The significantly positive effect of the Val-homozygote did not have a significantly positive effect on memory in the HC group, however. We found no significant association between BDNF polymorphisms and plasma concentrations of BDNF. The plasma BDNF was more likely to be associated with clinical characteristics than it was with memory indices in the BD-II group. The impaired memory function in BD-II patients might be dependent upon the association between the BDNF Val66Met polymorphism and peripheral BDNF levels.

Genetic Variants of the Brain-Derived Neurotrophic Factor and Metabolic Indices in Veterans With Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is a trauma and stressor related disorder that may develop after exposure to an event that involved the actual or possible threat of death, violence or serious injury. Its molecular underpinning is still not clear. Brain-derived neurotrophic factor (BDNF) modulates neuronal processes such as the response to stress, but also weight control, energy and glucose homeostasis. Plasma BDNF levels and a functional BDNF Val66Met (rs6265) polymorphism were reported to be associated with PTSD, as well as with increased body mass index (BMI) and dyslipidaemia in healthy subjects and patients with cardio-metabolic diseases, but these results are controversial. The other frequently studied BDNF polymorphism, C270T (rs56164415), has been associated with the development of different neuropsychiatric symptoms/disorders. As far as we are aware, there are no data on the association of BDNF Val66Met and C270T polymorphisms with metabolic indices in PTSD. Due to high rates of obesity and dyslipidaemia in PTSD, the aim of this study was to elucidate the association of BDNF Val66Met and C270T polymorphisms with BMI and lipid levels in veterans with PTSD. We hypothesized that BDNF variants contribute to susceptibility to metabolic disturbances in PTSD. The study included 333 Caucasian males with combat related PTSD, diagnosed according to DSM-5 criteria. Genotyping of the BDNF Val66Met and C270T polymorphisms was performed using the real-time PCR method. Results were analyzed using hierarchical multiple linear regression and the Mann–Whitney test, with p-value corrected to 0.005. The results showed that BDNF Val66Met and BDNF C270T polymorphisms were not significantly associated with BMI, total cholesterol, LDL-cholesterol, HDL-cholesterol or triglycerides. Although the BDNF C270T polymorphism was nominally associated only with HDL-cholesterol in veterans with PTSD, this significance disappeared after controlling for the effect of age. Namely, slightly higher plasma HDL values in T allele carriers, compared to CC homozygotes, were associated with differences in age. Our results, controlled for the critical covariates, revealed that BDNF Val66Met and C270T were not significantly associated with metabolic indices in veterans with PTSD and that these genetic variants do not contribute to susceptibility to metabolic disturbances in PTSD.

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.

Rs6265 polymorphism in brain-derived neurotrophic factor (Val/Val and Val/Met) promotes proliferation of bladder cancer cells by suppressing microRNA-205 and enhancing expression of cyclin J.

In this study, we evaluated the effect of rs6265 polymorphism on the expression of brain-derived neurotrophic factor (BDNF) and relevant downstream targets, as well as the involvement of this polymorphism in bladder cancer. A computational analysis and luciferase assays were used to explore the interaction among BDNF, miR-205, and cyclin J (CCNJ). Real-time polymerase chain reaction (RT-PCR) and Western blot analysis were carried out to determine the effect of rs6265 polymorphism on the expression of BDNF and relevant downstream genes. BDNF directly inhibited miR-205 expression but enhanced the expression of CCNJ, which was identified as a virtual target gene of miR-205. Furthermore, the inhibitory effect of BDNF carrying the Val genotype, defined as BDNF (Val), on miR-205 expression was much stronger than that of BDNF (Met), while the inductive effect of BDNF (Val) on CCNJ expression was much weaker than that of BDNF (Met). miR-205 and CCNJ small interfering RNA (siRNA) were found to reduce cell proliferation and arrest the cells in G0/G1 phase. In addition, miR-205 expression in patients carrying BDNF genotyped as Met/Met (defined as Met/Met group) was much higher than patients carrying BDNF genotyped as Val/Val and Val/Met (defined as Val/Val group and Val/Met group). As an inhibitor of CCNJ expression, the inhibitory effect of miR-205 was much higher in the Met/Met group than that in the Val/Val and Val/Met groups. In summary, we suggested that the rs6265 polymorphism in BDNF upregulates the expression of CCNJ in bladder cancer via the inhibition of miR-205 expression, which leads to the promoted proliferation of bladder cancer cells.

Global epigenetic analysis of BDNF Val66Met mice hippocampus reveals changes in dendrite and spine remodeling genes.

Brain-derived neurotrophic factor (BDNF), a neurotrophin highly expressed in the hippocampus, plays crucial roles in cognition, neuroplasticity, synaptic function, and dendritic remodeling. The common human Val66Met polymorphism of BDNF has been implicated in the pathophysiology of neuropsychiatric and neurodegenerative disorders, and in the outcome of pro-adaptive and therapeutic treatments. Altered gene-expression profile has been previously shown in BDNF Val66Met knock-in mice, which recapitulate the phenotypic hallmarks of individuals carrying the BDNF Met allele. The aim of this study was to investigate the impact of the BDNF Val66Met polymorphism in the knock-in mouse model on two hippocampal epigenetic marks for transcriptional repression and activation, respectively: trimethylation of lysine 27 on histone H3 (H3K27me3) and acetylation of histone H3 (AcH3), using a genome-wide approach. Chromatin immunoprecipitation followed by deep sequencing of immunoprecipitated DNA (ChIP-Seq) was carried out with specific antibodies for H3K27me3 and AcH3. Our results revealed broad alteration of H3K27me3 and AcH3 marks association profiles in BDNFMet/Met , compared to BDNFVal/Val mice. Bioinformatics analysis showed changes in several biological functions and related pathways, affected by the presence of the polymorphism. In particular, a number of networks of functional interaction contained BDNF as central node. Quantitative PCR analysis confirmed epigenetically related significant changes in the expression of five genes: Dvl1, Nos3, Reln, Lypd6, and Sh3gl2. The first three are involved in dendrite and spine remodeling, morphological features altered in BDNFMet/Met mice. This work in homozygous knock-in mice shows that the human BDNF Val66Met polymorphism induces an array of histone H3 epigenetic modifications, in turn altering the expression of select genes crucial for structural and functional neuronal features.

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.

Amygdala subnuclei and healthy cognitive aging.

Amygdala is a group of nuclei involved in the neural circuits of fear, reward learning, and stress. The main goal of this magnetic resonance imaging (MRI) study was to investigate the relationship between age and the amygdala subnuclei volumes in a large cohort of healthy individuals. Our second goal was to determine effects of the apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF) polymorphisms on the amygdala structure. One hundred and twenty-six healthy participants (18-85 years old) were recruited for this study. MRI datasets were acquired on a 4.7 T system. Amygdala was manually segmented into five major subdivisions (lateral, basal, accessory basal nuclei, and cortical, and centromedial groups). The BDNF (methionine and homozygous valine) and APOE genotypes (ε2, homozygous ε3, and ε4) were obtained using single nucleotide polymorphisms. We found significant nonlinear negative associations between age and the total amygdala and its lateral, basal, and accessory basal nuclei volumes, while the cortical amygdala showed a trend. These age-related associations were found only in males but not in females. Centromedial amygdala did not show any relationship with age. We did not observe any statistically significant effects of APOE and BDNF polymorphisms on the amygdala subnuclei volumes. In contrast to APOE ε2 allele carriers, both older APOE ε4 and ε3 allele carriers had smaller lateral, basal, accessory basal nuclei volumes compared to their younger counterparts. This study indicates that amygdala subnuclei might be nonuniformly affected by aging and that age-related association might be gender specific.

The Influence of the Val66Met Polymorphism of Brain-Derived Neurotrophic Factor on Neurological Function after Traumatic Brain Injury

Functional outcomes after traumatic brain injury (TBI) vary widely across patients with apparently similar injuries. This variability hinders prognosis, therapy, and clinical innovation. Recently, single nucleotide polymorphism (SNPs) that influence outcome after TBI have been identified. These discoveries create opportunities to personalize therapy and stratify clinical trials. Both of these changes would propel clinical innovation in the field. This review focuses on one of most well-characterized of these SNPs, the Val66Met SNP in the brain-derived neurotrophic factor (BDNF) gene. This SNP influences neurological function in healthy subjects as well as TBI patients and patients with similar acute insults to the central nervous system. A host of other patient-specific factors including ethnicity, age, gender, injury severity, and post-injury time point modulate this influence. These interactions confound efforts to define a simple relationship between this SNP and TBI outcomes. The opportunities and challenges associated with personalizing TBI therapy around this SNP and other similar SNPs are discussed in light of these results.

Associations between Variants in BDNF/BDNFOS Gene and Lumbar Disc Herniation Risk among Han Chinese People

Lumbar disc herniation (LDH) is a low back pain disorder and associated with several single nucleotide polymorphisms (SNPs). However, the role of brain-derived neurotrophic factor (BDNF) and BDNFOS gene in LDH susceptibility remains unknown. To examine whether the variants contribute to LDH, 7 SNPs were genotyped in 380 patients and 692 healthy controls among Han Chinese population. Multiple genetic models, stratification by age/gender and haploview analysis was used by calculating odds ratio (OR) and 95% confidence intervals (CIs). Rs11030064 in BDNFOS gene was associated with modified susceptibility for LDH at age ≤50 years but three loci (rs6265, rs11030104 and rs10767664) of BDNF gene increased LDH risk at age >50 years. Further, rs11030096 polymorphism in BDNFOS gene was associated with LDH the increased susceptibility of LDH in females. Haplotype analysis shown that haplotype “GCC” in the block (rs988712, rs7481311, and rs11030064) increased LDH risk (OR = 1.49, 95% CI = 1.06–2.10, p = 0.022) at age ≤50 years. However, there was no significant association between BDNF/BDNFOS gene and LDH risk in the overall before stratified analysis. For the first time, our results provide evidence on polymorphism of BDNF / BDNFOS gene associated with LDH risk in Chinese Han population.

Effect of the polymorphism BDNF rs6265 G/A in Mexican outpatient children with autism spectrum disorders

Introduction. The study of autistic spectrum disorders (ASD) at the genetic level is extremely important to understand their origin. In Mexico, there are few works addressed from this perspective. Objective. We investigated the role of the Brain Derived Neurotrophic Factor ( BDNF ) gene variant rs6265 G/A for single nucleotide polymorphism analysis in Mexican children with ASD using a case-control association design. Method. We made a pilot study by case-control analysis adjusting by gender, age, and ancestry. Results. Our study found no association between the BDNF rs6265 gene polymorphism and ASD [ p = .419, OR = 1.597 (.514, 4.967)]. Discussion and conclusion. Worldwide, the results of case-control association studies with the rs6265 of BDNF are controversial and do not always replicate. This may be due to the ethnicity of our population and additional factors not studied in the present work. Our study suggests that the SNP rs6265 is not contributing for ASD susceptibility in Mexican population.

Critical Issues in BDNF Val66Met Genetic Studies of Neuropsychiatric Disorders.

Neurotrophins have been implicated in the pathophysiology of many neuropsychiatric diseases. Brain-derived neurotrophic factor (BDNF) is the most abundant and widely distributed neurotrophin in the brain. Its Val66Met polymorphism (refSNP Cluster Report: rs6265) is a common and functional single-nucleotide polymorphism (SNP) affecting the activity-dependent release of BDNF. BDNF Val66Met transgenic mice have been generated, which may provide further insight into the functional impact of this polymorphism in the brain. Considering the important role of BDNF in brain function, more than 1,100 genetic studies have investigated this polymorphism in the past 15 years. Although these studies have reported some encouraging positive findings initially, most of the findings cannot be replicated in following studies. These inconsistencies in BDNF Val66Met genetic studies may be attributed to many factors such as age, sex, environmental factors, ethnicity, genetic model used for analysis, and gene–gene interaction, which are discussed in this review. We also discuss the results of recent studies that have reported the novel functions of this polymorphism. Because many BDNF polymorphisms and non-genetic factors have been implicated in the complex traits of neuropsychiatric diseases, the conventional genetic association-based method is limited to address these complex interactions. Future studies should apply data mining and machine learning techniques to determine the genetic role of BDNF in neuropsychiatric diseases.

Correlations of Four Genetic Single Nucleotide Polymorphisms in Brain-Derived Neurotrophic Factor with Posttraumatic Stress Disorder.

ObjectiveTo investigate the correlations of four genetic single nucleotide polymorphisms (SNPs) of brain-derived neurotrophic factor (BDNF) with posttraumatic stress disorder (PTSD). MethodsA total of 300 patients with sporadic PTSD and 150 healthy subjects (the control group) were selected according to the diagnostic criteria of PTSD (DSM-IV), and the genotypes of the BDNF SNPs G-712A, C270T, rs6265, and rs7103411 were detected by polymerase chain reaction and direct DNA sequencing to determine intergroup differences in the genotypes and allele frequencies; the p values were corrected with the permutation test. ResultsThe genotypes and allele frequencies of the SNPs G-712A, rs6265, and rs7103411 of BDNF showed no significant intergroup differences (p>0.05). However, the genotype and allele frequencies of C270T showed significant differences between the PTSD group and the control group (p<0.05). ConclusionThe SNP C270T of BDNF may be associated with PTSD. Individuals carrying the polymorphic T allele of C270T may be more likely to suffer from PTSD.

Targeted Genotyping Identifies Susceptibility Locus in Brain-derived Neurotrophic Factor Gene for Chronic Postsurgical Pain.

The purpose of this study was to evaluate the association between single-nucleotide polymorphisms and chronic postsurgical pain. Using GoldenGate genotyping assays, we genotyped 638 polymorphisms within 54 pain-related genes in 1,152 surgical patients who were enrolled in our Persistent Pain after Surgery Study. Patients were contacted by phone to determine whether they had chronic postsurgical pain at 12 months. Polymorphisms identified were validated in a matched cohort of 103 patients with chronic postsurgical pain and 103 patients who were pain free. The functions of targeted polymorphisms were tested in an experimental plantar incisional nociception model using knock-in mice. At 12 months after surgery, 246 (21.4%) patients reported chronic postsurgical pain. Forty-two polymorphisms were found to be associated with chronic postsurgical pain, 19 decreased the risk of pain, and 23 increased the risk of pain. Patients carrying allele A of rs6265 polymorphism in brain-derived neurotrophic factor (BDNF) had a lower risk of chronic postsurgical pain in the discovery and validation cohorts, with an adjusted odds ratio (95% CI) of 0.62 (0.43 to 0.90) and 0.57 (0.39 to 0.85), respectively. Age less than 65 yr, male sex, and prior history of pain syndrome were associated with an increased risk of pain. Genetic polymorphisms had higher population attributable risk (7.36 to 11.7%) compared with clinical risk factors (2.90 to 5.93%). Importantly, rs6265 is a substitution of valine by methionine at amino acid residue 66 (Val66Met) and was associated with less mechanical allodynia in BDNF mice compared with BDNF group after plantar incision. This study demonstrated that genetic variant of BDNF rs6265G>A is associated with decreased risk of chronic postsurgical pain.

Meta-Analysis on the Association between Brain-Derived Neurotrophic Factor Polymorphism rs6265 and Ischemic Stroke, Poststroke Depression

Ischemic stroke is a multifactorial neurologic injury that causes mortality and disability worldwide. Poststroke depression is the most important neuropsychiatric consequence of stroke. Brain-derived neurotrophic factor is a neurotrophin family member that plays key role in regulating neuron survival and differentiation. Studies found a polymorphism in brain-derived neurotrophic factor gene (rs6265) may associate with the ischemic stroke and poststroke depression risk. However, the results are inconclusive and inconsistent. In the present meta-analysis, the database PubMed, Embase, Cochrane Central Register of Controlled Trials, CNKI, and Chinese Biomedical Literature Database were searched until July 9, 2017. Seven studies with 1287 cases and 1032 controls were included for the meta-analysis of ischemic stroke, and five studies with 272 cases and 503 controls were included for poststroke depression. The results indicated that the GG genotype of brain-derived neurotrophic factor is related to a significantly lower risk of ischemic stroke in the homozygous and dominant models (odds ratio = .57 and .80, respectively). No significant relation was found between rs6265 and poststroke depression. Thus, brain-derived neurotrophic factor rs6265 might be recommended as a predictor of susceptibility of ischemic stroke. However, the results of this meta-analysis should be interpreted with caution because of the heterogeneity between studies and low sample size. Further studies are needed to evaluate the associations between rs6265 and poststroke depression, especially in Caucasians, with large sample size.

Suicide attempt, clinical correlates, and BDNF Val66Met polymorphism in chronic patients with schizophrenia.

Recent evidence suggests the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of suicidal behavior. Because schizophrenia patients usually have high suicide rates and numerous studies have suggested that BDNF may contribute to the psychopathology of schizophrenia, we hypothesized that the functional polymorphism of BDNF (Val66Met) was associated with suicide attempts in patients with schizophrenia in a Chinese Han population. This polymorphism was genotyped in 825 chronic schizophrenia patients with (n = 123) and without (n = 702) suicide attempts and 445 healthy controls without a history of suicide attempts using a case-control design. The schizophrenia symptoms were assessed by the Positive and Negative Syndrome Scale. There were no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls. However, we found the Val allele (p = .023) and the Val/Val genotypes (p = .058) to be associated with a history of suicide attempts. Moreover, some clinical characteristics, including age and cigarettes smoked each day, interacted with the BDNF gene variant and appeared to play an important role in suicide attempts among schizophrenia patients. The BDNF Val66Met polymorphism itself and its interaction with some clinical variables may influence suicide attempts among schizophrenia patients. (PsycINFO Database Record