BDNF Val66Met多态性在抑郁障碍中的作用

近5年来,随着对抑郁障碍研究的深入,新的发现如海马神经发生异常机制的明确、脑源性神经营养因子(brain-derivedneurotrophic factor,BDNF)在抑郁障碍中的保护作用,以及抑郁症患者脑功能连接异常等,均证实神经网络改变是抑郁发生的早期事件。临床实践表明目前一线抗抑郁药物普遍存在起效延迟、有效率仅在50%左右、不良反应较多等问题,因此,研究者们希望找到新的     

抑郁症患者脑源性神经营养因子Val66Met多态性与血清浓度的关系

目的探讨脑源性神经营养因子（BDNF）基因Val66Met多态性与抑郁症之同的关系以及Val66Met多态性是否影响血清BDNF浓度。方法对76例未经药物治疗的抑郁症患者和50例正常人,用限制性片段长度多态性方法分析Val66Met多态性,采用酶联吸附反应方法对血清BDNF浓度进行检测。结果（1）抑郁症患者血清BDNF浓度（24．7±12．7）ng／m1显著低于正常对照组（36．6±16．4）pg／m｜,差异有统计学意义（P〈0．01）;（2）抑郁症组和对照组之间的Val66Met多态性位点的等位基因频率和基因型分布差异无统计学意义（P〉0．05）;（3）在抑郁症组和对照组,Val／Met＋Met／Met基因型组与Val／Val基因型相比,血清BDNF浓度差异无统计学意义（P〉0．05）。结论抑郁症患者存在较低的血清BDNF水平,BDNF基因Val66Met多态性与抑郁症之间无相关性,Val66Met多态性对血清BDNF水平浓度无明显影响。     

弥漫性轴索损伤BDNF及其Val66Met基因多态性与认知功能的相关性研究

目的探讨弥漫性轴索损伤（DAI）（Ⅱ型）患者伤后1个月血清脑源性神经营养因子（BDNF）水平及其Val66Met基因多态性与认知功能的关系。 方法选取晋江市医院神经外科自2015年8月至2020年8月收治的106例DAI（Ⅱ型）患者为病例组,选择同期来本院体检的105名健康体检者为对照组,采用第二版洛文斯顿作业疗法认知量表（LOTCA）、蒙特利尔评估量表中文版（MoCA）分别评估对照组和病例组伤后1个月时的认知功能;采用酶联免疫吸附试验测定2组研究对象的血清BDNF水平;聚合酶链反应-限制性片段长度多态性分析BDNF Val66Met基因多态性;多元逐步回归法分析病例组整体认知功能与BDNF及BDNF Val66Met基因多态性的相关性。 结果病例组伤后1个月相同基因亚型血清BDNF浓度均低于对照组,差异有统计学意义（P<0.05）;病例组Val/Val亚型血清BDNF浓度高于Val/Met、Met/Met亚型,差异有统计学意义（P<0.05）,而Val/Met和Met/Met亚型血清BDNF浓度比较差异无统计学意义（P>0.05）。病例组患者3种基因亚型伤后1个月的LOTCA和MoCA评分均低于对照组,差异有统计学意义（P<0.05）;病例组Val/Val亚型评分高于Val/Met、Met/Met评分,差异有统计学意义（P<0.05）,而Val/Met和Met/Met亚型评分比较,差异无统计学意义（P>0.05）。DAI（Ⅱ型）整体认知水平与BDNF Val66Met基因多态性、BDNF浓度具有线性回归关系（F=11.417,P<0.001）,其具有一定的相关性（|β|=0.966、0.877;r=0.569、0.579）。 结论BDNF可影响DAI认知功能,其BDNF Val66Met基因多态性可能是影响DAI认知功能的风险因素之一。     

脑源性神经营养因子Val66Met功能基因多态性与抗抑郁剂疗效

目的：探讨脑源性神经营养因子（BDNF）Val66Met功能基因多态性与抗抑郁剂临床疗效的相关性。方法：302例抑郁症患者给予抗抑郁剂治疗8周。于治疗前和治疗2、4、6、8周后采用汉密尔顿抑郁量表（HAMD）评定抑郁严重程度和疗效。以治疗后HAMD总分≤7分为临床痊愈,将302例患者分为痊愈组160例和未痊愈组142例,抽取患者静脉血,采用Illumina GoldenGate定制芯片分析BDNFVal66Met基因多态性并进行基因分型。结果：痊愈组基因型分布A/A31例（19.4%）、A/G92例（57.5%）和G/G37例（23.1%）,未痊愈组分别为28例（19.7%）、78例（54.9%）和36例（25.4%）（χ2=0.054,P=0.817）;痊愈组等位基因频率分布A154例（48.1%）和G166例（51.9%）,未痊愈组分别为134例（47.2%）和150例（52.8%）（χ2=0.247,P=0.884）。3种BDNFVal66Met基因型患者间在性别、年龄、受教育年限、病程、发病次数、有无精神疾病家族史、HAMD基线及减分率上差异均无统计学意义（P均〉0.05）。结论：BDNFVal66Met基因多态性不是影响抗抑郁剂治疗近期疗效的主要因素。     

脑卒中后抑郁与脑源性神经营养因子基因Val66Met单核苷酸多态性的相关性研究

目的探讨脑卒中后抑郁(PSD)与脑源性神经营养因子(BDNF)基因Val66Met单核苷酸多态性(SNP)的相互关系。方法选择86例PSD患者为PSD组,68例脑卒中无PSD患者为无PSD组,另选择46名健康者为对照组。3组研究对象年龄及性别基本匹配。采用酶联免疫吸附法检测BDNF浓度和等位基因特异性聚合酶链反应(A-S PCR)技术检测BDNF基因Val66Met位点SNP的分布。结果 PSD组和无PSD组间BDNF表达差异有统计学意义(t=-2.038,P=0.043);两组间基因型频率(χ2=0.340,P=0.844)和等位基因频率(χ2=0.036,P=0.849)差异均无统计学意义。结论 BDNF表达与PSD发生相关,但BDNF基因Val66Met位点SNP与PSD未发现有相关关系。     

脑源性神经营养因子基因Val66Met多态性与重性抑郁障碍患者认知功能的关系

目的:探讨脑源性神经营养因子(BDNF)基因Val66Met多态性与重性抑郁障碍认知功能的关系。方法:对100例重性抑郁障碍患者进行认知功能测验和事件相关电位P300检查,同时检测BDNF基因多态性。结果:Val/Val基因型患者大部分认知测验成绩优于Met/Met基因型,差异均有统计学意义(P均<0.01);Met/Met基因型患者P3潜伏期(LATP3)长于Val/Val基因型[分别(304.3±11.8)ms和(293.3±15.7)ms],P3波幅(AMPP3)低于Val/Val基因型[分别(5.9±1.9)μV和(7.4±2.1)μV],差异均有统计学意义(P<0.05或P<0.01)。结论:BDNF基因Val66Met多态性可能与重性抑郁障碍患者认知功能损害有关。     

BDNF基因启动子区多态性与散发性阿尔茨海默病的相关性研究

目的研究脑源性神经营养因子(BDNF)基因启动子区单核苷酸多态性与散发性阿尔茨海默病(SAD)发病的相关性。方法随机选取10例正常对照组及10例SAD患者进行BDNF基因启动子区-1～-2812bp测序,针对所发现的启动子区单核苷酸多态性(SNP),利用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的方法对328例正常对照者及292例SAD患者进行基因型检测后进行病例-对照关联分析。结果在中国北方汉族人群的BDNF基因启动子区发现1个SNP:-2467G/A(rs908867)。其等位基因及基因型分布在两组间无显著性差异(P值分别为0.10和0.27),经APOEε4分层后它们的分布在两组间也无显著性差异(P>0.05)。结论中国北方汉族人群BDNF基因启动子区的遗传变异可能与SAD发病无关。     

抑郁症患者脑源性神经营养因子Va166Met多态性与血清浓度的关系

目的 探讨脑源性神经营养因子(BDNF)基因Va166Met多态性与抑郁症之间的关系以及Va166Met多态性是否影响血清BDNF浓度.方法 对76例未经药物治疗的抑郁症患者和50例正常人,用限制性片段长度多态性方法分析Va166Met多态性,采用酶联吸附反应方法对血清BDNF浓度进行检测.结果 (1)抑郁症患者血清BDNF浓度(24.7±12.7)ng/ml显著低于正常对照组(36.6±16.4)pg/ml,差异有统计学意义(P＜0.01);(2)抑郁症组和对照组之间的Va166Met多态性位点的等位基因频率和基因型分布差异无统计学意义(P＞0.05);(3)在押郁症组和对照组,Val/Met+Met/Met基因型组与Val/Val基因型相比,血清BDNF浓度差异无统计学意义(P＞0.05).结论 抑郁症患者存在较低的血清BDNF水平,BDNF基因Val66Met多态性与抑郁症之间无相关性,Va166Met多态性对血清BDNF水平浓度无明显影响.     

BDNF基因多态性与精神分裂症发病及临床症状的 相关性

目的 探讨BDNF基因rs2030324和rs11030101多态性与精神分裂症发病及临床症状的关 系。方法 于2017年1月—2018年1月由齐齐哈尔市精神卫生中心招募200例精神分裂症患者（病例组） 及200 例健康对照（对照组）纳入研究。每位研究对象抽取5 ml 静脉血提取基因组DNA，对rs2030324 和 rs11030101 两个位点上下游500 bp 的序列设计引物，进行PCR 扩增，比较rs2030324 和rs11030101 两个 位点在两组人群中的基因频率分布及基因型分布。对病例组采用阳性与阴性症状量表（PANSS）评估临 床症状，分析PANSS 评分与不同基因型的相关性。结果 病例组和对照组在rs2030324 和rs11030101 两个位点基因频率分布和基因型分布均具有统计学意义（P＜ 0.05）。该两个位点的A 等位基因，都是 精神分裂症的易感基因，OR 值=1.532、1.391；95%CI=1.154～2.034、1.027～1.883。rs11030101 位点AT 基因型的患者与PANSS 阴性症状评分相关，AT基因型的患者阴性症状评分最高。结论 BDNF 基因 rs2030324、rs11030101 位点多态性与汉族人群精神分裂症的发病具有相关性，该两个位点的等位基因 A 均可能是精神分裂症发病的易感等位基因。rs11030101 位点多态性可能影响精神分裂症的临床表现。     

Role of BDNF Val66Met functional polymorphism in temporal lobe epilepsy

Various studies suggested that brain-derived neurotrophic factor (BDNF) gene polymorphisms contributed to the development of many neurological disorders. However, whether BDNF Val66Met polymorphism is associated with epilepsy remains controversial. In our study, we tried to investigate the effects of this functional polymorphism on the occurrence of temporal lobe epilepsy (TLE) and its clinical phenotypes. Case-control studies were employed to study the association between BDNF Val66Met polymorphism and TLE, as well as its clinical phenotypes, and magnetic resonance imaging examinations and voxel-based morphometry analyses were carried out for further study. Our results showed that the frequency of Met allele was found to be lower in the TLE patients compared with the control subjects (43.9% vs. 48.6%, P = 0.012, OR = 1.21, 95% CI = 1.04–1.41), and the frequency of Met66 allele carriers in the TLE with hippocampal sclerosis was significantly lower than those non-carriers (20.5% vs. 29.1%, P = 0.040). However, we failed to find the difference between different genotypes and hippocampal asymmetry. Our findings suggested that BDNF Val66Met polymorphism might be correlated with epileptogenesis, and Met66 allele might play a protective role against the occurrence of TLE.     

The Val66Met polymorphism of the BDNF gene in anorexia nervosa: New data and a meta-analysis

Abstract

Objectives. The Val66Met polymorphism (rs6265) of the BDNF gene is a non-synonymous polymorphism, previously associated with anorexia nervosa (AN). Methods. We genotyped rs6265 in 235 patients with AN and 643 controls. Furthermore, we performed a systematic review of all case–control and family-based studies testing this SNP in AN, and combined the results in a meta-analysis. Results. The results of the case–control study were non-significant. For the meta-analysis, nine studies were identified (n_cases = 2,767; n_controls = 3,322, n_trios = 53) and included. Primarily, the analyses indicated an association with OR of 1.11 (P = 0.024) in the allelic contrast, and OR of 1.14 (P = 0.025) for the dominant effect of the Met allele. However, additional analyses revealed that the first published study (from those included in the meta-analysis) overly influenced the pooled effect size (possibly due to a phenomenon known as a winner's curse). When this case–control study was replaced by a trio study (n_trios = 293) performed on a largely overlapping sample, the effect size became smaller and non-significant, both for the allelic contrast (OR = 1.07, P = 0.156) and the dominant effect (OR = 1.07, P = 0.319). The quality of included studies was good and there was no significant heterogeneity across the effect sizes. Conclusions. Our analyses indicate that the BDNF Val66Met variant is not associated with AN at detectable levels.     

Genetic Role of BDNF Val66Met and 5-HTTLPR Polymorphisms on Depressive Disorder

Objective

We investigated possible association between depressive disorders and BDNF Val66Met and 5-HTTLPR. Brain derived neurotrophic factor (BDNF) gene and serotonin transporter (SLC6A4) gene are promising candidate genes for depressive disorders. It has been suggested that BDNF promotes the survival and differentiation of serotonergic neurons and that serotonergic transmission exerts powerful control over BDNF gene expression.

Methods

Final analyses were performed on 186 patients with depressive disorders and 1032 controls. Val66Met polymorphism of BDNF gene and 5-HTTLPR polymorphism of serotonin transporter gene were genotyped and allele and genotypic associations on the diagnosis of depression and age at onset of depression were analyzed.

Results

The 5-HTTLPR was positively associated with depressive affected status in the total sample and in females (p=0.038 for allelewise, p=0.015 for genotype-wise associations), but, not in males. The BDNF Val66Met showed no association with depression. BDNF Val66Met and 5-HTTLPR alone were not associated with age at onset of depression. Additional analysis on the interaction between BDNF Val66Met and 5-HTTLPR found a significant association with age at onset of depression in the entire patient group. This association was also found in the female but not in the male patient group. None of the positive results survived Bonferroni correction for multiple testing.

Conclusion

This result suggested that BDNF Val66Met and 5-HTTLPR may contribute to depressive disorders in a complex way and that the genetic effect could differ by gender. Further studies with large number of patients will be necessary.     

Smoking and BDNF Val66Met polymorphism in male schizophrenia: A case-control study

Some recent studies show an association between a functional polymorphism of BDNF gene (Val66Met) and the susceptibility to nicotine dependence and we hypothesized that this polymorphism was associated with smoking in both schizophrenia patients and healthy controls. The BDNF Val66Met gene polymorphism was genotyped in 690 chronic male schizophrenia patients (smoker/nonsmoker = 522/169) and 628 male controls (smoker/nonsmoker = 322/306) using a case-control design. Nicotine dependence (ND) was assessed by the cigarettes smoked per day (CPD), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). Patients also were rated on the Positive and Negative Syndrome Scale (PANSS). The results showed no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls or between smokers and nonsmokers in either patients or healthy controls alone. In patient groups, however, the smokers with the Met allele had significantly higher HSI scores (Met/Met: 2.8 ± 1.7 vs. Met/Val: 2.2 ± 1.7 vs. Val/Val: 2.0 ± 1.6, p < 0.01) and a trend toward a significantly higher FTND score (p = 0.09) than those with the Val/Val genotype. In addition, the smokers showed significantly lower PANSS negative symptom and total scores, longer duration of illness and more hospitalizations (all p < 0.05). In the control group, the smokers with the Met allele started smoking significantly earlier than those with the Val/Val genotype (both p < 0.05). These results suggest that the BDNF Val66Met polymorphism may affect a smoker's response to nicotine in both schizophrenia and healthy controls from a Chinese Han population, but with differential effects in different aspects of smoking behaviors.     

Influence of the BDNF Val66Met polymorphism on coping response to stress in patients with advanced gastric cancer

Objective

Coping with cancer is an important determinant of psychological morbidity, quality of life, and treatment adherence in cancer patients. The aim of this study was to elucidate the association between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and coping response to stress in patients diagnosed with advanced gastric cancer.

Methods

Ninety-one subjects (60 males, 31 females) recently diagnosed with advanced gastric cancer were recruited. Coping style and distress level were examined using the Mini-Mental Adjustment to Cancer (Mini-MAC) scale and Hospital Anxiety and Depression Scale, and genotyping was evaluated. To examine the temporal stability of the Mini-MAC scores, a 6-week follow-up evaluation was conducted in 72 patients, after completion of two chemotherapy cycles.

Results

Coping style to cancer significantly differed between the Met carriers of BDNF Val66Met and the Val/Val homozygotes. The Met carriers were significantly more anxious than the Val/Val homozygotes.

Conclusion

The present findings suggest that the BDNF Val66Met polymorphism may be involved in individual coping responses to cancer. The Met allele of BDNF Val66Met may be predictive of an anxious coping style in patients with advanced cancer.     

The study of BDNF Val66Met polymorphism in Chinese schizophrenic patients

Accumulating evidence showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. Recent studies have reported that the Val66Met polymorphism of the BDNF gene may be associated with susceptibility for schizophrenia and age of onset of this disease, with mix results. In the present study, the BDNF Val66Met gene polymorphism was examined in 387 inpatients (259 men and 128 women) meeting the DSM-IV criteria for schizophrenia and unrelated 365 healthy controls (255 men and 110 women). The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS). Age of onset was defined as the age at which the psychotic symptoms first appeared. Our results showed that genotype frequency distributions and allelic frequencies did not differ between patients and controls. No interaction was found between sex and genotypes. Analysis of covariance (ANCOVA) showed a significance of the BDNF Val66Met genotypes on the age of onset (F = 3.76, p < 0.02), after adjusting sex, age and duration of illness. Furthermore, ANCOVA showed that the significance of the BDNFVal66Met genotypes on age of onset was increased comparing the Val66Met heterozygotes with the combination of Val66Val and Met66Met homozygotes (F = 5.85, p < 0.01). Our results suggest that the BDNF Val66Met polymorphism may not contribute directly to the susceptibility to schizophrenia, but to the onset of the disease. Furthermore, our results show the heterozygous effect of the BDNF Val66Met gene on the clinical variability of schizophrenia phenotype.     

Exploring the association between BDNF Val66Met polymorphism and suicidal behavior: Meta-analysis and systematic review

Suicide is a serious worldwide health problem of critical consequences. Nowadays genetic factors are considered to be an important cause of suicide. The association between Val66Met (rs6265) polymorphism of the BDNF gene and suicide behavior has been increasingly studied. The aim of this study was to perform a meta-analysis in order to unravel the possible association between BDNF gene Val66Met polymorphism and suicide behavior. These meta-analysis and systematic review were performed using 23 articles that searched for a genetic association between Val66Met and suicide behavior, including 4532 cases and 5364 control subjects. The association was analyzed following the models: allelic, homozygous, heterozygous, dominant and recessive. Also, analyses by ethnicity (Caucasian and Asian populations) were done following the same four models. When the overall population was evaluated, we found no evidence of association between the polymorphism Val66Met of BDNF (rs6265) and suicide behavior (Met vs. Val: OR: 1.01; 95% CI = 0.92–1.10). However, a significant increased risk was found in the subgroup analysis by ethnicity in Caucasian populations (Met-Met vs. Met-Val + Val-Val: OR: 1.96; 95% CI = 1.58–2.43) and Asian populations (Val-Val vs. Val-Met + Met: OR: 1.36; 95% CI = 1.04–1.78). Our results suggest there is no association between the BDNF gene Val66Met (rs6265) and suicide behavior in the overall population. However, ethnic differences can be observed and the BDNF Val66Met might increase the risk for suicide behavior in Asian and Caucasian populations. Further studies with larger samples are necessary in order to have conclusive outcomes.     

Kynurenine pathway is altered in BDNF Val66Met knock-in mice: Effect of physical exercise

The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been correlated with increased predisposition to develop cognitive and psychiatric disorders, and with a reduced response to some therapeutic treatments. However, the mechanisms underlying these impairments are currently not completely understood. Remarkably, kynurenine pathway alterations have also been implicated in cognitive and psychiatric disorders. Moreover, recent evidence suggests that physical exercise may promote beneficial effects by controlling kynurenine metabolism in the muscle.The aim of the present study was to assess whether the kynurenine pathway was differentially regulated in sedentary and exercising wild-type (BDNF^Val/Val) and homozygous knock-in BDNF Val66Met (BDNF^Met/Met) mice. We found that plasma and hippocampal levels of kynurenic acid and the hippocampal mRNA levels of IDO1 and KAT2 protein levels were increased in BDNF^Met/Met mice and were not modulated by physical exercise. On the contrary, KAT1 protein levels in the gastrocnemius muscle were reduced, whereas MCP1 mRNA in the gastrocnemius muscle and GFAP protein in the hippocampus were increased in BDNF^Met/Met mice compared to BDNF^Val/Val mice, and reduced by physical exercise. Physical exercise increased plasmatic kynurenine levels only in BDNF^Met/Met mice, and protein levels of KAT1 and KAT4 in the gastrocnemius muscle and hippocampus respectively, regardless of the genotype. Finally, we found that physical exercise was able to enhance the hippocampal-dependent memory only in the BDNF^Val/Val mice. Overall our results showing an overactivation of the kynurenine pathway in the BDNF^Met/Met mice may suggest a possible mechanism underlying the cognitive deficits reported in the BDNF Val66Met carriers.