Rs6265 Single Nucleotide Polymorphism Research Articles

Advancing age and the rs6265 BDNF SNP are permissive to graft-induced dyskinesias in parkinsonian rats

The rs6265 single nucleotide polymorphism (SNP) in the gene for brain-derived neurotrophic factor is a common variant that alters therapeutic outcomes for individuals with Parkinson’s disease (PD). We previously investigated the effects of this SNP on the experimental therapeutic approach of neural grafting, demonstrating that young adult parkinsonian rats carrying the variant Met allele exhibited enhanced graft function compared to wild-type rats and also exclusively developed aberrant graft-induced dyskinesias (GID). Aging is the primary risk factor for PD and reduces graft efficacy. Here we investigated whether aging interacts with this SNP to further alter cell transplantation outcomes. We hypothesized that aging would reduce enhancement of graft function associated with this genetic variant and exacerbate GID in all grafted subjects. Unexpectedly, beneficial graft function was maintained in aged rs6265 subjects. However, aging was permissive to GID induction, regardless of genotype, with the greatest incidence and severity found in rs6265-expressing animals.

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

IntroductionThe 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. ObjectiveWe 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 MethodsFifteen 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. ResultsOutcomes 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. ConclusionsGenotyping 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.

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.

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. 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. 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). 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.

Neurostructural correlates of BDNF rs6265 genotype in youth bipolar disorder

Brain-derived neurotrophic factor (BDNF) rs6265single-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 rs6265Met allele with neurostructural phenotypes in youth BD. Caucasian youth (N=99; 13-20years; 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. 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. 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.

The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats

Prevalent in approximately 20% of the worldwide human population, the rs6265 (also called ‘Val66Met’) single nucleotide polymorphism (SNP) in the gene for brain-derived neurotrophic factor (BDNF) is a common genetic variant that can alter therapeutic responses in individuals with Parkinson’s disease (PD). Possession of the variant Met allele results in decreased activity-dependent release of BDNF. Given the resurgent worldwide interest in neural transplantation for PD and the biological relevance of BDNF, the current studies examined the effects of the rs6265 SNP on therapeutic efficacy and side-effect development following primary dopamine (DA) neuron transplantation. Considering the significant reduction in BDNF release associated with rs6265, we hypothesized that rs6265-mediated dysfunctional BDNF signaling contributes to the limited clinical benefit observed in a subpopulation of PD patients despite robust survival of grafted DA neurons, and further, that this mutation contributes to the development of aberrant graft-induced dyskinesias (GID). To this end, we generated a CRISPR knock-in rat model of the rs6265 BDNF SNP to examine for the first time the influence of a common genetic polymorphism on graft survival, functional efficacy, and side-effect liability, comparing these parameters between wild-type (Val/Val) rats and those homozygous for the variant Met allele (Met/Met). Counter to our hypothesis, the current research indicates that Met/Met rats show enhanced graft-associated therapeutic efficacy and a paradoxical enhancement of graft-derived neurite outgrowth compared to wild-type rats. However, consistent with our hypothesis, we demonstrate that the rs6265 genotype in the host rat is strongly linked to development of GID, and that this behavioral phenotype is significantly correlated with neurochemical signatures of atypical glutamatergic neurotransmission by grafted DA neurons.

BDNF rs6265 Polymorphism and Its Methylation in Patients with Stroke Undergoing Rehabilitation.

Brain-Derived Neurotrophic Factor (BDNF) and its rs6265 single nucleotide polymorphism (SNP) play an important role in post-stroke recovery. We investigated the correlation between BDNF rs6265 SNP and recovery outcome, measured by the modified Barthel index, in 49 patients with stroke hospitalized in our rehabilitation center at baseline (T0) and after 30 sessions of rehabilitation treatment (T1); moreover, we analyzed the methylation level of the CpG site created or abolished into BDNF rs6265 SNP. In total, 11 patients (22.4%) were heterozygous GA, and 32 (65.3%) and 6 (12.2%) patients were homozygous GG and AA, respectively. The univariate analysis showed a significant relationship between the BDNF rs6265 SNP and the modified Barthel index cut-off (χ2(1, N = 48) = 3.86, p = 0.049), considering patients divided for carrying (A+) or not carrying (A−) the A allele. A higher percentage of A− patients obtained a favorable outcome, as showed by the logistic regression model corrected by age and time since the stroke onset, compared with the A+ patients (OR: 5.59). At baseline (T0), the percentage of BDNF methylation was significantly different between GG (44.6 ± 1.1%), GA (39.5 ± 2.8%) and AA (28.5 ± 1.7%) alleles (p < 0.001). After rehabilitation (T1), only patients A− showed a significant increase in methylation percentages (mean change = 1.3, CI: 0.4–2.2, p = 0.007). This preliminary study deserves more investigation to confirm if BDNF rs6265 SNP and its methylation could be used as a biological marker of recovery in patients with stroke undergoing rehabilitation treatment.

BDNF rs6265 Variant Alters Outcomes with Levodopa in Early-Stage Parkinson's Disease.

Disease outcomes are heterogeneous in Parkinson's disease and may be predicted by gene variants. This study investigated if the BDNF rs6265 single nucleotide polymorphism (SNP) is associated with differential outcomes with specific pharmacotherapy treatment strategies in the "NIH Exploratory Trials in PD Long-term Study 1" (NET-PD LS-1, n = 540). DNA samples were genotyped for the rs6265 SNP and others (rs11030094, rs10501087, rs1491850, rs908867, and rs1157659). The primary measures were the Unified Parkinson's Disease Rating Scale (UPDRS) and its motor component (UPDRS-III). Groups were divided by genotype and treatment regimen (levodopa monotherapy vs levodopa with other medications vs no levodopa). T allele carriers were associated with worse UPDRS outcomes compared to C/C subjects when treated with levodopa monotherapy (+ 6 points, p = 0.02) and to T allele carriers treated with no levodopa treatment strategies (UPDRS: + 8 points, p = 0.01; UPDRS-III: + 6 points, p = 0.01). Similar effects of worse outcomes associated with levodopa monotherapy were observed in the BDNF rs11030094, rs10501087, and rs1491850 SNPs. This study suggests the levodopa monotherapy strategy is associated with worse disease outcomes in BDNF rs6265 T carriers. Pending prospective validation, BDNF variants may be precision medicine factors to consider for symptomatic treatment decisions for early-stage PD patients.

Brain Derived Neurotrophic Factor (BDNF) Val66Met Single Nucleotide Polymorphism (rs6265) is Associated With Decreased Functional Outcome After Traumatic Brain Injury: A Multicenter Cohort Study

Abstract INTRODUCTION Brain-derived neurotrophic factor (BDNF) is a common neurotrophin important to neuronal survival and plasticity. We aim to elucidate the associations between the BDNF single nucleotide polymorphism (SNP) Val66Met (rs6265) and 3-mo outcome after traumatic brain injury (TBI). METHODS TBI subjects from the prospective, multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study conducted across 3 US Level I trauma centers were eligible. All subjects presented to emergency department &lt; 24 h of injury and received a brain computed tomography (CT) scan as part of clinical care. Patients aged = 18-yr with Marshall CT Score 1 to 3 were included. Associations between BNDF rs6265 (Val/Val vs Met-carriers), demographic/injury factors, and 3-mo Glasgow Outcome Scale-Extended (GOSE) were analyzed. Multivariable regression was performed for BDNF and outcomes, controlling for age, sex, education, GCS, CT, and polytrauma. Odds ratios (OR) and 95% CIs are shown. Significance was assessed at P &lt; .05. RESULTS A total of 180 TBI subjects were aged 45.5 ± 18.3-yr, 68.5% male, and 81% Caucasian. Subjects were GCS 13 to 15, with 40% CT-positive and 16% polytrauma, which did not differ by BDNF. In all 64% were Val/Val (vs 36% Met-carriers). At 3-mo, functional impairment (GOSE &lt; 7) was present in 33% (Val/Val: 26%, Met-carrier: 46%, P = .006), and 28% were unable to resume baseline work capacity (Val/Val: 21%, Met-carrier: 40%, P = .006). These results were conserved when stratified by CT. In CT-negative subjects, Met-carriers were at risk for functional impairment (univariate-OR = 3.0, 95% CI [1.1-7.4]) and inability to return to baseline work (RTBW; univariate-OR = 3.0 [1.2-7.4]). For CT-positive subjects, results were similar for functional impairment (univariate-OR = 2.4 [0.9-6.3]) and inability to RTBW (univariate-OR = 2.4 [0.9-6.3]). On multivariable analysis, BDNF Met-carriers were at elevated risk for functional impairment (OR = 2.5 [1.2-5.0]) and inability to RTBW (OR = 2.6 [1.2-5.4]). CONCLUSION BDNF rs6265 SNP may associate with TBI outcomes, with Met-carriers at increased risk of 3-mo functional impairment and inability to RTBW. Future confirmatory studies are needed.

BDNF Val66Met genetic variation and its plasma level in patients with morbid obesity: A case-control study

Obesity is a major public health concern worldwide. Genetic, behavioral, and environmental factors contribute to the multifactorial etiology of obesity. Evidence suggests an association between human Brain-Derived Neurotrophic Factor (BDNF) Val66Met single nucleotide polymorphism (SNP) and obesity. Reduced plasma BDNF levels have also been reported in patients with eating disorders and obesity. We aimed to evaluate the BDNF Val66Met (rs6265) SNP and also plasma BDNF levels in morbidly obese patients compared with healthy normal controls in southern Iran. One hundred morbidly obese patients and one hundred eight healthy normal controls were enrolled. Blood-derived DNA samples were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and confirmed by DNA sequencing. Plasma BDNF levels were evaluated using a commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kit for human BDNF. Data analysis was performed by SPSS software, version 18.0. Genotype distribution was not significantly different between obese patients and controls. However, plasma BDNF levels were significantly lower in obese patients compared with controls. Interestingly, a significant association was found between BDNF Val66Met SNP and plasma BDNF levels. No relationship was observed between BDNF Val66Met SNP and all assessed demographic and clinical characteristics of obese patients. It seems that plasma BDNF levels were associated with both obesity and BDNF Val66Met SNP. However, this association was not found between BDNF Val66Met SNP and obesity. Further studies with larger sample sizes are needed for more detailed assessment of this genetic variation as a potential biomarker for obesity.

Effect of Met66 allele of the BDNF rs6265 SNP on regional gray matter volumes in patients with multiple sclerosis: A voxel-based morphometry study

The rs6265 single nucleotide polymorphism (SNP) is a genetic variation in the brain-derived neurotrophic factor ( BDNF) gene wherein the presence of the A-allele at rs6265 causes replacement of a valine (Val) at position 66 by methionine (Met). We reported recently that the Met66 allele was associated with lower brain damage as evidenced by measurement of gray matter (GM) volume in multiple sclerosis (MS) patients. The objective of this study was to determine the voxel-wise regional GM differences between the Val66Val and Met66 allele groups in MS patients by using voxel-based morphometry (VBM)-optimized analysis corrected for lesion misclassification in Statistical Parametric Mapping (SPM5). High-resolution 3D-T1-weighted SPGR images from a total of 188 MS patients were acquired on a 1.5 T MRI. The Val66Val group included 129 MS patients and the Met66 allele group (comprised of Val66Met or Met66Met genotypes) included 59 MS patients. The SPM analysis of covariance tool was used to assess group differences after controlling for variation in head size, MS disease course and gender. VBM analysis did not yield significant family wise error (FWE) corrected results. This was also confirmed with the non-parametric analysis using threshold-free cluster enhancement (TFCE) method. However, the results from VBM as well as the TFCE analyses ( p < 0.001, uncorrected) showed higher GM volume in the cingulate of MS patients with Met66 allele than those with Val66Val. Future studies are warranted to investigate longitudinally possible protective role of the Met66 allele of the BDNF rs6265 SNP in relation to specific GM regions.

Preservation of gray matter volume in multiple sclerosis patients with the Met allele of the rs6265 (Val66Met) SNP of brain-derived neurotrophic factor

To investigate the association of the rs6265 (Val66Met) single nucleotide polymorphism (SNP) of brain-derived neurotrophic factor (BDNF) with brain morphometry and functional status as measured by quantitative magnetic resonance imaging (MRI) and neurocognitive testing in multiple sclerosis (MS) patients. BDNF is released by neurons and by immune cells in MS brain. The rs6265 SNP variation of BDNF causes substitution of valine (Val) for methionine (Met) and interferes with activity-dependent BDNF secretion. A total of 209 treated MS patients (161 females; 48 males) underwent clinical brain MRI and were genotyped for the BDNF rs6265 Val66Met SNP. A subset of 108 patients had neurocognitive testing for processing speed, memory and executive function. The MRI measurements included T2 and T1-lesion volume (LV); normalized brain volume measures of whole brain (WB) volume, white and gray matter volume (NWMV and NGMV) and the diffusion-weighted imaging measure of WB mean parenchyma diffusivity (MPD). The Met66 allele status was positively associated with NGMV (P = 0.015, standardized beta = 0.15) and negatively associated with T2-LV (P = 0.041, standardized beta = -0.14). There were no significant associations between Met66 allele status and T1-LV, NWMV or MPD. On the Paced Serial Addition Test (PASAT), a trend (P = 0.057) favoring the Met66 allele group was observed. There were no significant associations between Met66 allele status and other neurocognitive measures. The BDNF Met66 allele is associated with lower damage as evidenced by measurement of NGMV and T2-LV in MS patients.