BDNF基因多态性与海洛因成瘾者美沙酮维持治疗反应关联性分析

目的:探究中国汉族人群中脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)基因3个位点rs988748、rs2030324和rs6265单核苷酸多态性(Single nucleotide polymorphism,SNP)与海洛因成瘾者美沙酮维持治疗反应的关联性。方法:用病例对照设计,收集820例美沙酮维持治疗患者既往吸毒史和目前治疗情况,结合多重PCR技术、Mass ARRAY i PLEX单碱基延伸技术和基质辅助激光解吸附电离飞行时间质谱分析技术进行SNP分型,将受试对象分为美沙酮维持治疗反应好和差组,使用SPSS 21.0统计软件分析数据。结果:BDNF基因3个位点(rs988748、rs2030324和rs6265)的等位基因、基因型和单体型在两组间分布差异均无统计学意义(P>0.05)。结论:尚未发现BDNF基因3个SNP位点(rs988748、rs2030324和rs6265)与美沙酮维持治疗反应之间存在相关性。     

DA、5-HT、BNDF相关基因多态性与甲基苯丙胺成瘾者暴力行为及情绪特征的关联性研究

目的:研究DA、5-HT、BNDF相关基因多态性与甲基苯丙胺成瘾者暴力行为及情绪特征的关联性。方法:获的吸毒人员600人,通过MOAS评分确定最终纳入暴力组还是非暴力组,采用PCR-DNA测序方法检测DA、5-HT、BNDF相关基因多态性。结果:卡方检验结果显示,5-HT2A受体基因rs6313、MAOA rs1137070、DRD4受体基因rs1800955及BDNF基因rs6265位点基因多态性与甲基苯丙胺成瘾者的暴力行为之间存在关联(P <0. 05),多因子降维法(MDR)分析显示暴力组与非暴力组"rs6313-rs626"、"同伴暴力-rs6313"及"父母吸毒/酗酒-rs6313-rs6265"的两种组合模型有统计学意义(P <0. 05)。结论:同伴暴力行为、父母吸毒/酗酒可能联合DA、5-HT、     

BDNF基因多态性与散发性阿尔茨海默病患者认知功能的相关性研究

目的探讨脑源性神经营养因子（BDNF）基因功能性多态（rs6265）与散发性阿尔茨海默病（SAD）发病的相关性。方法选取58例散发性阿尔茨海默患者（SAD组）与52例健康老年人（对照组）,用聚合酶链反应-限制性片段长度多态性技术,对BDNF基因rs6265,进行基因型检测,同时利用酶联免疫吸附技术对两组患者的血清BDNF水平进行检测。结果在〈60岁的人群中,等位基因（χ^2=6.0595,P=0.013）及基因型（χ^2=6.0826,P=0.0478）在两组人群中的分布差异有统计学意义,并且SAD的AA基因型患者的血清BDNF水平最低[（14.32±4.21）ng/ml,F=7.2545,P=0.0016]。结论 BDNF基因功能性多态rs6265与SAD发病相关,并且影响其血清BDNF的表达。     

DRD1基因和OPRM1基因功能区多态性与海洛因依赖的关系

目的探讨物质依赖候选基因多巴胺D1受体(Dopamine receptor D1,DRD1)和μ阿片受体(μ-Opioid receptor,OPRM1)基因多态性与海洛因依赖之间是否存在关联。方法采用直接测序的方法对中国西安汉族海洛因依赖者和正常对照群体的DRD1和OPRM1基因进行检测,并对OPRM1基因的rs1799971位点与海洛因依赖关联研究进行了Meta分析。结果 DRD1基因共发现rs1799914、rs4532、rs53263个多态性位点,OPRM1基因共发现rs1799971和rs6912029两个多态性位点;关联分析未发现这5个单核苷酸多态性位点与海洛因依赖之间存在关联;Meta分析结果也不支持OPRM1基因的A118G多态性位点与海洛因依赖的关联性,但这一结果尚未能排除基因上位性效应的可能影响。结论 rs1799914、rs4532、rs5326、rs1799971和rs6912029位点及其构成的单倍型与海洛因依赖之间可能不存在关联。     

氨氯地平降压疗效与L型钙离子通道α1C亚基的基因多态性的关系

目的研究氨氯地平的降压疗效与L型钙离子通道α1C亚基的基因(CACNA1C)单核苷酸多态性(SNPs)间的关联。方法纳入181例服用氨氯地平的原发性高血压患者,用PCR-直接测序法,对CACNA1C基因单核苷酸多态性(SNPs)rs1051375、rs2238032、rs7311382、rs2239050、rs2239127、rs2239128和rs2239129等位点进行基因分型;用多元线性回归方法,分析SNPs位点基因型与氨氯地平降压疗效间的关系。结果调整基线血压、体质量指数、血脂异常、性别和年龄的影响后,rs2238032G/T位点基因多态性与氨氯地平的降压疗效明显相关(△SBP:P=0.02;△DBP:P=0.01);rs1051375A/G、rs7311382C/T、rs2239050G/C、rs2239127C/T、rs2239128C/T和rs2239129C/T位点虽均显示出基因型间氨氯地平降压疗效的差异,但均无统计学意义(P>0.05)。结论 CAC-NA1C基因rs2238032位点基因多态性与原发性高血压患者服用氨氯地平的降压效果明显相关。     

健康汉族人群Nm23基因多态性对其mRNA表达的影响

目的:探讨中国湖北地区汉族健康人群Nm23基因单核苷酸多态性(SNPs)(rs2302254、rs2318785、rs11868380及rs34214448)与mRNA表达量的关系。方法:收集200例中国湖北地区汉族健康体检人群的血液样本,采用实时荧光TaqMan-MGB探针等位基因分型技术进行多态性检测和实时荧光定量PCR技术进行mRNA相对表达量测定。应用非参检验方法评估基因型与mRNA相对表达量的关系。结果:rs2302254位点CC基因型者Nm23 mRNA表达量显著低于TT及CT基因型者(P=0.000);rs2318785位点AA基因型者Nm23 mRNA表达量显著低于GG及GA基因型(P=0.000);rs34214448位点GG基因型者Nm23 mRNA表达量显著低于TT及GT基因型者(P=0.000)。本研究并未发现rs11868380位点多态性与基因表达量间的联系(P=0.140)。结论:Nm23基因rs2302254、rs2318785及rs34214448单核苷酸多态性会影响mRNA相对表达量。     

载脂蛋白M基因多态性与冠心病的相关性

目的 检测载脂蛋白M(ApoM)基因rs805264位点、rs707922位点和rs707921位点的多态性在贵州省汉族人群的分布,探讨其多态性与冠心病(CHD)的相关性.方法 采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测220例CHD患者和195例对照组的基因型,以酶法测定血脂水平.结果 ApoM基因rs805264位点、rs707922位点及rs707921位点等位基因G-G-C、A-T-A紧密连锁,CHD组A-T-A单体型显著高于对照组.CHD组及对照组A-T-A单体型血清总胆固醇水平显著高于G-G-C单体型组,高密度脂蛋白胆固醇低于G-G-C单体型组.结论 贵州汉族人群ApoM基因rs805264、rs707922和rs707921位点A-T-A单体型可能是CHD的潜在遗传致病危险因子.     

IL-17A基因多态性与慢性阻塞性肺疾病易感性和严重程度的关系

目的 探讨IL-17A基因多态性与慢性阻塞性肺疾病(COPD)易感性和严重程度的关系.方法 选取稳定期COPD患者147例(COPD组)及同期健康体检者115例(对照组),采用基因测序法检测IL-17A基因rs2275913、rs1974226位点基因型及等位基因分布情况,采用多因素logistic回归分析COPD影响因素,并检测不同严重程度COPD患者基因型分布情况.结果 两组rs2275913位点的基因型和等位基因频率差异有统计学意义(P＜0.05),rs1974226位点基因型及等位基因频率差异无统计学意义(P＞0.05).与GG基因型相比,携带rs2275913位点AG基因型患COPD的风险下降(P＜0.05).不同严重程度COPD患者rs2275913和rs1974226位点基因型频率差异均无统计学意义(P＞0.05).结论 IL-17A基因rs2275913位点多态性可能与COPD的易感性有关,AG基因型是COPD的保护性因素,而与COPD严重程度无明显关系.     

Pin1基因多态性与喉鳞状细胞癌的相关性

目的探讨肽基脯氨酰顺反异构酶(Pin1)启动子区域的单核苷酸多态性(SNP)位点rs2233678、rs2233679与喉鳞状细胞癌(LSCC)的相关性。方法采用聚合酶链式反应-限制性内切酶片段长度多态性(PCR-RFLP)方法检测95例LSCC患者(病例组)及100例喉良性病变患者(对照组)外周血Pin1基因相关的SNP位点的差异;比较突变位点的基因型频率及等位基因型频率与患者颈淋巴结转移、临床分期的关系。结果 rs2233678多态性位点的基因型频率在病例组外周血中表达高于对照组(P<0.05),其基因型频率分布与淋巴结转移、TNM临床分期分组无关。rs2233679多态性位点的基因型频率分布在病例组和对照组中差异无统计学意义(P>0.05)。结论 rs2233678多态性位点与LSCC易感性有关。rs2233679多态性位点与LSCC易感性无关。     

哌甲酯治疗汉族儿童注意缺陷多动障碍疗效与GRIN2B基因多态性的关系

目的:探讨N-甲基-D-天冬氨酸受体2B亚单位基因(GRIN2B)rs1806201位点和rs1805247位点多态性与哌甲酯治疗汉族注意缺陷多动障碍(ADHD)患儿疗效的关系。方法:2017年1月至2019年1月驻马店市中心医院收治的100例ADHD患儿作为研究对象,进行2~4周的哌甲酯开放剂量治疗,获得最佳治疗反应。采用注意缺陷多动障碍诊断量表父母版(ADHDDS-P)评估ADHD症状。根据治疗前后量表评分,将疗效分为缓解、有效和无效。用TaqMan SNP基因分型技术检测GRIN2B基因rs1806201位点和rs1805247位点多态性。结果:100例患儿治疗后缓解40例,有效25例,无效35例。GRIN2B基因rs1806201位点TT型和CT型患儿治疗效果优于CC型患儿(P<0.05)。而rs1805247位点不同基因型患儿治疗效果的比较差异无统计学意义(P>0.05)。rs1806201位点TT和CT基因型患儿治疗后ADHDDS-P量表注意力缺陷评分、多动冲动评分和总分的减分值均高于CC型患儿(P<0.05),而rs1805247位点不同基因型患儿ADHDDS-P量表减分值比较差异无统计学意义(P>0.05)。结论:GRIN2B基因rs1806201位点多态性与哌甲酯治疗效果有关,而GRIN2B基因rs1805247位点多态性与哌甲酯治疗效果无关。GRIN2B基因rs1806201位点TT型和CT型ADHD患儿对哌甲酯的药物反应优于CC基因型患儿。     

The BDNF Val66Met Polymorphism Modulates the Generalization of Cued Fear Responses to a Novel Context

Brain-derived neurotrophic factor (BDNF) has a crucial role in activity-dependent synaptic plasticity and learning and memory. The human functional single-nucleotide BDNF rs6265 (Val66Met) polymorphism has been found to be associated with alteration in neural BDNF release and function correlating with altered emotional behavior. Here, we investigated for the first time the hypothesis that this polymorphism in humans modulates the context dependency of conditioned fear responses. Applying a new paradigm examining generalization of cued fear across contexts, 70 participants stratified for BDNF Val66Met polymorphism were guided through two virtual offices (context) in which briefly illuminated blue and yellow lights served as cues. In the fear context, one light (conditioned stimulus, CS+) but not the other light (CS−) was associated with an electric shock (unconditioned stimulus, US). In the safety context, both lights were presented too, but no US was delivered. During the test phase, lights were presented again both in learning contexts and in a novel generalization context without any US. All participants showed clear fear conditioning to the CS+ in the fear context as indicated by potentiation of startle responses and reports of fear. No fear reactions were found for the CS+ in the safety context. Importantly, generalization of fear responses indicated by the potentiation of startle response to the CS+ compared with the CS− in the novel context was evident only in the Met-carrying group. These are the first results to provide evidence in humans that BDNF modulates the generalization of fear responses. Such context-dependent generalization processes might predispose Met carriers for affective and anxiety disorders.     

Brain-derived neurotrophic factor gene polymorphisms: influence on treatment response phenotypes of major depressive disorder

Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family of neurotrophins, has pivotal roles in neuronal survival, proliferation, and synaptic plasticity in the brain. Both clinical and pharmacological studies have implicated the common single nucleotide polymorphism (SNP) at position 196, Val66Met in the pathophysiology of major depressive disorder (MDD), and antidepressant response. However, inconsistent results were found between Val66Met (rs6265) polymorphism and treatment response phenotypes in genetic association studies. The functional Val66Met polymorphism and seven other tagging SNP markers selected to capture the major allelic variations across BDNF locus were analyzed in depressed patients, treated with antidepressants, and 76 control patients. Two hundred and six patients with Diagnostic and Statistical Manual of Mental Disorders-IV MDD were recruited for this study and genotyped for eight BDNF tagging SNPs (rs11030096, rs925946, rs10501087,rs6265, rs12273363, rs908867, rs1491850, and rs1491851)to investigate the functional impact of genotypes/haplotypes in the susceptibility of depression and on treatment response. None of the eight SNPs, including the rs6265, were significantly associated with MDD after permutation correction. However, we found an association for rs10501087, rs6265 with nonresponse to antidepressant treatment (corrected permutation P:0.03599; 0.0399 and power: 0.1420; 0.1492, respectively).Analysis of each two-marker, three-marker, and four-marker sliding window haplotypes showed significance in haplotype combinations. Especially rs10501087 (C), rs6265 (A), and rs149,1850 (C) together or with the other SNP haplotypes showed a similar pattern in all treatment response phenotypes. Despite the limited power of analysis, our results suggest that these three SNPs may play a role in antidepressant treatment response phenotypes in MDD.     

Brain-derived neurotrophic factor/TrkB signaling in memory processes

Activity-dependent changes in synaptic strength are considered mechanisms underlying learning and memory. Brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity such as long-term potentiation. Recent experimental evidence supports the role of BDNF in memory processes: Memory acquisition and consolidation are associated with an increase in BDNF mRNA expression and the activation of its receptor TrkB. Genetic as well as pharmacologic deprivation of BDNF or TrkB impairs learning and memory. In a positively motivated radial arm maze test, activation of the TrkB/phosphatidylinositol-3 kinase (PI3-K) signaling pathway in the hippocampus is associated with consolidation of spatial memory through an activation of translational processes. In a negatively motivated passive avoidance test, mitogen-activated protein kinase (MAPK) is activated during acquisition of fear memory. Furthermore, recent findings suggest the importance of interaction between BDNF/TrkB signaling and NMDA receptors for spatial memory. A Src-family tyrosine kinase, Fyn plays a role in this interaction by linking TrkB with NR2B. These findings suggest that BDNF/TrkB signaling in the hippocampus plays a crucial role in learning and memory.     

Interaction of BDNF/TrkB signaling with NMDA receptor in learning and memory

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB play important roles in learning and memory. Memory acquisition is associated with an increase in BDNF mRNA and TrkB activation in specific brain areas. Pharmacologic and genetic deprivation of BDNF or TrkB results in an impairment of memory. Activation of the mitogen-associated protein kinase and phosphatidylinositol 3-kinase signaling pathways is involved in BDNF-dependent learning and memory. A frequent single nucleotide polymorphism in the targeting region of the human BDNF gene (val66met) is associated with poorer episodic memory and abnormal hippocampal neuronal function in humans. The interaction of BDNF/TrkB signaling with N-methyl-D-aspartate receptors is important for spatial learning and memory, and an Src-family tyrosine kinase Fyn may play a key role in this interaction by linking TrkB with NR2B.     

Alteration of the Centromedial Amygdala Glutamatergic Synapses by the BDNF Val66Met Polymorphism

Fear expression is mediated by an activation of the centromedial amygdala (CEm), the major output nucleus of the amygdaloid complex. Consistently, fear extinction is associated with an increased synaptic inhibition as well as a suppression of the excitability of the CEm neurons. However, little is known about the role of CEm glutamatergic synapses in fear regulation and anxiety-like behaviors. The BDNF Val66Met, a single-nucleotide polymorphism in the human BDNF gene, impairs fear extinction and leads to anxiety-like symptoms. To determine whether the BDNF Val66Met polymorphism affects the CEm excitatory synapses, we examined basal glutamatergic synaptic transmission and plasticity in the CEm neurons of BDNF Val66Met knock-in (BDNF^Met/Met) mice. The BDNF Val66Met single-nucleotide polymorphism exerted an opposite effect on non-NMDA and NMDA receptor transmission with a potentiation of the former and a suppression of the latter. In addition, the decay time of NMDA currents was decreased in BDNF^Met/Met mice, suggesting a modification of NMDA receptor subunit composition. Unlike the wild-type mice that exhibited a potentiation of non-NMDA receptor transmission following fear conditioning and a depotentiation upon fear extinction, BDNF^Met/Met mice failed to show this experience-dependent synaptic plasticity in the CEm neurons. Our results suggest that the elevated non-NMDA receptor transmission, the suppression of NMDA receptor transmission, and an impairment of synaptic plasticity in the CEm neurons might contribute to the fear extinction deficit and increased anxiety-like symptoms in BDNF Val66Met carriers.     

Association study between BDNF gene variants and Mexican patients with obsessive–compulsive disorder

Obsessive–compulsive disorder (OCD) is a psychiatric disorder whose etiology is not yet known. We investigate the role of three variants of the BDNF gene (rs6265, rs1519480 and rs7124442) by single SNP and haplotype analysis in OCD Mexican patients using a case–control and family-based association design. BDNF gene variants were genotyped in 283 control subjects, 232 OCD patients and first degree relatives of 111 OCD subjects. Single SNP analysis in case–control study showed an association between rs6265 and OCD with a high frequency of Val/Val genotype and Val allele (p=0.0001 and p=0.0001, respectively). Also, genotype and allele analysis of rs1519480 showed significant differences (p=0.0001, p=0.0001; respectively) between OCD and control groups. Haplotype analysis showed a high frequency of A–T (rs6265–rs1519480) in OCD patients compared with the control group (OR=2.06 [1.18–3.59], p=0.0093) and a low frequency of haplotype A–C in the OCD patients (OR=0.04 [0.01–0.16], p=0.000002). The family-based association study showed no significant differences in the transmission of any variant. Our study replicated the association between BDNF Val66Met gene polymorphism and OCD. Also, we found a significant association of rs1519480 in OCD patients compared with a control group, region that has never been analyzed in OCD. In conclusion, our findings suggest that BDNF gene could be related to the development of OCD.     

Association between the Val66Met polymorphism (rs6265/G196A) of the BDNF gene and cognitive performance with SSRI use in Arab Alzheimer’s disease patients

Brain derived neutrophic factor (BDNF) is a protein and a member of the neurotrophin family of growth factors, supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. The BDNF gene Val66Met polymorphism (rs6265/G196A) is responsible for BDNF synthesis that impact BDNF function that includes memory and cognition.This study investigated whether the BDNF gene Val66Met polymorphism (rs6265/G196A) is associated with cognitive function changes in both Alzheimer disease (AD) patients and elderly participants. In addition the impact of SSRI use on cognition improvement will be assessed. Healthy young, middle ages (25–59 years old) and elderly (more than 60 years old) participants (140) as well as 40 AD patients of whom are both of Saudi Arabian origin were recruited. The genotyping for the association study was performed by real-time PCR using Taqman chemistry in the ABI Prism 7900HT Sequence Detection System. Both Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) were used to assess cognitive function of healthy and AD participants, respectively.The findings showed that the BDNF Val66Met genotype distributions and allele frequencies have significant association with cognitive performance in both elderly control group and AD patients. The main findings showed that carriers of GG homozygotes (Val/Val) have superior cognitive performance among AD patients and elderly control subjects. In addition the use of SSRIs in 13 AD patients and 17 elderly participants positively improved cognitive function in elderly (p > 0.001) but not in AD patients (p = 0.1).     

Endocannabinoid modulation of fear responses: learning and state-dependent performance effects

Recently, disruption of the endogenous cannabinoid (endocannabinoid, eCB) system was found to impair extinction in delay and contextual fear conditioning models. However, conditioning procedures used in that work precluded investigation of possible eCB effects on acquisition of learned fear. We therefore examined the role of eCBs in modulating fear responses using multiple-trial versions of trace (hippocampal-dependent) and delay (amygdala-dependent) Pavlovian fear conditioning. By administering the CB1 receptor antagonist AM251 (5 mg/kg, i.p) to C57/Bl/6 mice at various times, we systematically identified the stages of learning and memory (i.e. acquisition, consolidation, recall and extinction) that are modulated by eCB signaling. During tone (CS) - footshock (US) conditioning, AM251 enhanced acquisition of freezing behavior for both trace- and delay-conditioning protocols. CB1 antagonism also enhanced generalized fear (baseline freezing) and cued (CS) freezing during memory recall tests in a state-dependent manner for both trace and delay conditioned animals. Furthermore, in trace-conditioned animals, AM251 impaired extinction performance of both cued and generalized fear. CB1 antagonism did not affect short-term memory (STM) or long-term memory (LTM) consolidation processes. Together, these results suggest that during acquisition and recall of aversive learning, eCBs prevent the expression and retention of inappropriate generalized and learned responses. These findings have important implications for the therapeutic use of CB1 antagonists.