BDNF基因多态性与冠心病共病抑郁的关联及其血小板活性机制

目的:探讨BDNF基因rs6265基因多态性与冠心病共病抑郁的关联,及其血小板活性机制。方法:采用HAMD-17对冠心病患者共病抑郁情绪进行筛查,收集到冠心病共病抑郁患者49例和冠心病未共病抑郁患者124例,收集患者临床资料,检测患者血小板活性,抽取患者外周静脉血,提取DNA,采用Taq Man探针SNP基因分型技术,对BDNF基因rs6265的单核苷酸多态性进行检测。结果:BDNF基因rs6265位点基因型分布频率,和等位基因频率在冠心病共病抑郁组与冠心病未共病抑郁组之间有显著差异,冠心病共病抑郁组突变基因型AA分布频率和突变等位基因A频率显著高于冠心病未共病抑郁组;且共病抑郁可使冠心病患者血小板比积更高。是否携带A等位基因对血小板活性的影响主效应均无统计学意义。结论:中国冠心病患者中携带BDNF rs6265等位基因A者对共病抑郁更易感,但本研究未发现其通过作用于血小板活性而参与共病机制。     

BDNF Val66Met基因多态性与家庭功能的关联分析

目的:探讨脑源性营养因子BDNF Val66Met(rs6265)基因多态性与个体感知的家庭亲密度之间的关系。方法:选取BDNF基因rs6265多态性位点,采用聚合酶链式反应和连接酶检测反应(PCR-LDR)检查技术,测定142名青少年罪犯和116名普通中学生的BDNF基因多态性分布,并应用家庭适应性和亲密度量表中文版(FACESIICV)评估家庭功能。结果:等位基因A携带者的家庭实际亲密度和适应性显著低于GG基因型者,其亲密度和适应性的不满意度则显著高于GG基因型者。一般线性模型中,在控制组别、受教育年限及年龄后,rs6265仍与家庭亲密度、亲密度不满度显著相关(P=0.001)。结论:等位基因A携带者所感受到的家庭成员间的情感联系和家庭适应能力较GG基因型者弱,对家庭亲密度和适应性更为不满。     

脑源性神经营养因子基因与生活事件交互作用对抑郁自杀未遂的影响

目的探讨脑源性神经营养因子(BDNF)基因与生活事件交互作用对于抑郁障碍自杀未遂患者的影响。方法收集伴自杀未遂行为的重性抑郁障碍患者和无自杀未遂的重性抑郁障碍患者各80例,评定汉密尔顿抑郁量表、生活事件量表,采用聚合酶链反应技术(PCR)对BDNF基因多态性进行基因分型,应用MDR软件包分析基因-环境交互作用。结果①与重性抑郁障碍无自杀未遂组相比,重性抑郁障碍自杀未遂组rs6265 AA基因型频率较高,差异具有统计学意义(χ2=7.380,P=0.025);自杀未遂组A等位基因频率较高,差异具有统计学意义(χ2=4.081,P=0.043)。②MDR结果显示,BDNF rs6265基因多态性与负性生活事件存在交互作用模型,该模型的检验样本误差较小(0.4686),交叉验证一致性为10/10,符号检验P0.001。结论 BDNF rs6265基因多态性与负性生活事件之间存在交互作用,该交互作用与重性抑郁障碍自杀未遂行为发生相关。     

抑郁症患者无抽搐电休克治疗的疗效与脑源性神经营养因子基因多态性

目的:探讨抑郁症患者脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)基因两个单核苷酸多态性位点的多态性与无抽搐电休克治疗(modified electroconvulsive therapy,MECT)疗效的关系。方法:采用病例对照研究,研究组为110例符合美国精神障碍诊断统计手册第4版(Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition,DSM-IV)抑郁症诊断标准的门诊及住院患者,对照组为100名正常人。患者入组后连续接受MECT8次,使用汉密顿抑郁量表(Hamilton Depression Rating Scale for Depression,HRSD)进行抑郁严重程度及疗效评估。运用PCR扩增及测序的方法,分析BD-NF基因rs6265、rs7103411单核苷酸多态性的分布,分析rs6265、rs7103411基因型及等位基因频率分布与MECT疗效的关系。结果:BDNF基因rs6265、rs7103411位点基因型及等位基因频率在对照组与患者组间的差异无统计学意义,MECT后2个位点基因型及rs7103411等位基因频率在不同疗效组间的差异无统计学意义。rs6265位点A等位基因频率和G等位基因频率在减分率≥50%组分别为47.9%、52.1%;在减分率<25%组分别为27.5%、72.5%,两组比较差异有统计学意义(P<0.05),且A等位基因对MECT反应好于G等位基因(OR=1.740,95%CI:1.022~2.963)。结论:病情严重的抑郁症患者BDNF基因rs6265位点A等位基因可能与无抽搐电休克治疗效果有关,A等位基因携带者接受MECT的疗效较G等位基因携带者好。     

BDNFrs6265基因多态性与冠心病患者伴发焦虑的关联

目的:探讨BDNFrs6265基因多态性与冠心病共病焦虑的关联。方法:采用HAMA-14量表对冠心病患者共病焦虑进行筛查,收集到冠心病共病焦虑患者71例和冠心病未共病焦虑患者194例,收集患者临床资料,采用HAMD-17量表对冠心病患者抑郁进行评估,抽取患者外周静脉血,提取DNA,采用TaqMan探针SNP基因分型技术,对BDNFrs6265的单核苷酸多态性进行检测,采用SPSS17.0对数据进行分析。结果:BDNFrs6265基因型分布频率,在冠心病共病焦虑组与冠心病未共病焦虑组之间无显著差异(χ~2=5.51,P=0.064),但是冠心病共病焦虑组突变等位基因Met频率显著高于冠心病未共病焦虑组(χ~2=4.60,P=0.032);回归分析显示:携带BDNFrs6265等位基因Met和HAMD-17阻滞因子、HAMD-17失眠因子对冠心病共病焦虑有显著预测作用(P均0.05)。结论:中国冠心病患者中BDNF rs6265 Met等位基因携带者对共病焦虑更易感。携带BDNF rs6265 Met等位基因和HAMD-17阻滞因子,以及HAMD-17失眠因子,可以预测冠心病患者是否发生焦虑。     

创伤后应激障碍症状阳性者的人格特征与创伤后应激障碍预后的关系

目的:了解洪灾13年后创伤后应激障碍症状阳性者的预后情况,以及人格特征与创伤后应激障碍预后的关系。方法:本研究为横断面研究,采用多阶段随机抽样法,对200例经历1998-1999年湖南省洞庭湖区特大洪灾且经2000年流行病学调查被归类为创伤后应激障碍症状阳性的灾民再次进行调查。采用创伤后应激障碍量表平民版(PCL-C)对创伤后应激障碍再次进行筛查,实际入组184例,将研究对象分为康复组(n=162例)和PTSD症状阳性组(n=22例);采用艾森克人格问卷简式量表中国版(EPQ-RSC)测查两组的人格特征。用logistic回归模型分析人格特征与创伤后应激障碍预后的关系。结果:洪灾13年后PTSD症状持续阳性比率为12.0%(22/184)。康复组EPQ-RSC外向人格得分高于PTSD症状阳性组[(51.8±10.7)vs.(45.1±13.2),P0.05],神经质人格得分低于PTSD症状阳性组[(46.5±10.1)vs.(58.3±12.2),P0.05]。Logistic回归分析显示,在调整性别、年龄等变量后,神经质高是创伤后应激障碍症状持续阳性的危险因素(OR=3.63,95%CI:1.05~12.54)。结论:洪灾后创伤后应激障碍症状阳性持续存在的情况值得重视,神经质人格与创伤后应激障碍预后相关。     

AQP7和AQP9基因多态性与中国汉族人群2型糖尿病的相关性研究CSCD

目的探讨水通道蛋白7(aquaporin 7, AQP7)以及水通道蛋白9(aquaporin 9, AQP9)基因单核苷酸多态性(single nucleotide polymorphism, SNP)与中国汉族人群患2型糖尿病(type 2 diabetes mellitus, T2DM)的相关性。方法随机纳入1194例T2DM个体和1274例非糖尿病个体(non-diabetic, NDM)进行对照研究, 采用MassArray质谱基因分型方法对3个SNP位点(AQP7基因rs3758269、AQP9基因rs16939881和rs57139208)进行基因分型。评估以上3个SNP位点与T2DM的相关性;探讨NDM组SNP位点处不同基因型与糖脂代谢指标的关联。结果 AQP7基因rs3758269、AQP9基因rs16939881和rs57139208的等位基因频率及基因型频率在T2DM组和NDM组中的分布无统计学差异(P > 0.05);且分析结果显示不同遗传模式与T2DM无相关性(P > 0.05)。在NDM组中, AQP7基因rs3758269、AQP9基因rs16939881和rs57139208的不同基因型与糖脂代谢指标无相关性(P > 0.05)。结论 AQP7基因rs3758269和AQP9基因rs16939881和rs57139208与中国汉族人群T2DM遗传易感性无关。     

PTSD相关基因的研究进展

创伤后应激障碍(PTSD)是环境因素与个体基因共同作用的结果,PTSD和很多基因的多态性有着密切的联系,如dopamine receptor D2(DRD2)、serotonin-transporterlinked polymorphic region(5-HTTLPR)、FK506 binding protein 5(FKBP5)等基因的多态性在PTSD患者中的表达。PTSD患者中枢神经多巴胺系统可能存在损伤或缺陷,导致暂时或持续性的精神症状出现。5-羟色胺功能紊乱增强患者的易激惹性、兴奋性与好斗性,导致其环境适应能力下降。FKBP5低表达可能是PTSD发生的危险因子。以上三种基因的多态性可以增加PTSD的易感性,这些分析将有助于干预PTSD的发生及预后。     

应对方式在震后青少年人格特质与PTSD症状间的中介作用

目的:考察人格特质与应对方式对汶川地震幸存青少年出现的创伤后应激障碍(简称PTSD)症状的影响,并检验应对方式在人格特质与PTSD症状间的中介作用。方法:在汶川地震发生半年后,选取四川省绵竹市某乡镇学校4～8年级学生共168人参加此次研究。施测量表包括事件冲击量表儿童版、艾森克人格问卷青少年版以及中学生应对方式量表。结果:神经质、情绪型应对与PTSD症状相关显著,相关系数分别为0.399(P<0.001),0.367(P<0.001);两变量共解释PTSD症状20.1%的变异(Adjusted R2=0.192)。中介效应分析发现情绪型应对部分中介了神经质对PTSD症状的影响。结论:人格影响创伤后应激障碍。情绪型应对部分中介神经质对PTSD症状的影响。     

内皮固有型一氧化氮合酶基因单核苷酸多态性与冠心病的相关性研究

探讨内皮固有型一氧化氮合酶(ecNOS)基因的单核苷酸多态性(SNP)与冠心病(CAD)的相关性.提取107例CAD患者和132名健康对照者外周血有核细胞DNA,应用荧光标记单碱基延伸分型技术及寡核苷酸微阵列芯片杂交技术检测ecNOS基因的2个标签SNP(tag SNP)rs7830和rs3918188.结果发现CAD组rs7830的CC基因型频率和C等位基因频率明显低于健康对照组(P＜0.05).两组rs3918188的基因型频率及等位基因频率无统计学差异(P＞0.05).通过对2个SNP进行单倍型分析发现,CAD组和健康对照组的单倍型频率具有统计学差异(P<0.05).结果提示ecNOS基因 rs7830多态性变异及由rs7830和rs3918188构建的CA、AA单倍型是CAD的遗传危险因素.     

Polymorphisms of brain-derived neurotrophic factor associated with heroin dependence

Brain-derived neurotrophic factor (BDNF) promotes synaptic remodeling and modulates the function of other neurotransmitters. It also plays a role in the reward response to many drugs, including heroin. To identify genetic variants associated with heroin dependence, we compared four single nucleotide polymorphisms (SNPs, rs13306221, rs6265, rs56164415, and rs16917204) of the BDNF gene in 487 subjects with heroin dependence and 492 healthy individuals. The analysis revealed the G allele of rs6265 was significantly more common in heroin-dependent subjects than in the healthy controls (P=0.001 after Bonferroni correction). Among heroin-dependent individuals, the onset of dependence was significantly earlier in individuals with GG or GA genotypes compared to AA individuals (P<0.01). Additionally, we found that the G allele of rs13306221 was significantly more frequent in heroin-dependent subjects than in controls (P=0.005 after Bonferroni correction). These findings support a role of BDNF rs6265 and rs13306221 polymorphisms in heroin dependence and may guide future studies to identify other genetic risk factors for heroin dependence.     

Computed tomography analysis of the association between the SH2B1 rs7498665 single-nucleotide polymorphism and visceral fat area

Visceral fat accumulation has an important role in increasing morbidity and mortality rate by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of obesity have been identified by genome-wide association studies in Caucasian populations. We genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography (CT) for measuring visceral fat area (VFA) and subcutaneous fat area (SFA), for the following single-nucleotide polymorphisms (SNPs): NEGR1 rs2815752, SEC16B rs10913469, TMEM18 rs6548238, ETV5 rs7647305, GNPDA2 rs10938397, BDNF rs6265 and rs925946, MTCH2 rs10838738, SH2B1 rs7498665, MAF rs1424233, and KCTD15 rs29941 and rs11084753. In the additive model, none of the SNPs were significantly associated with body mass index (BMI). The SH2B1 rs7498665 risk allele was found to be significantly associated with VFA (P=0.00047) but not with BMI or SFA. When the analysis was performed in men and women separately, no significant associations with VFA were observed (P=0.0099 in men and P=0.022 in women). None of the other SNPs were significantly associated with SFA. Our results suggest that there is a VFA-specific genetic factor and that a polymorphism in the SH2B1 gene influences the risk of visceral fat accumulation.     

Sustained phosphorylation and activation of protein kinase B correlates with brain-derived neurotrophic factor and insulin stimulated survival of cerebellar granule cells.

Brain-derived neurotrophic factor (BDNF) and insulin promote the survival of 6-7 day old post-natal rat cerebellar granule cells. Previous studies using the PI3 kinase inhibitor, wortmannin and the over-expression of protein kinase B (PKB) have indicated that both PI3 kinase and PKB activation are central for insulin-stimulated survival of these neurones. Here we report that BDNF, insulin and epidermal growth factor (EGF) all cause the phosphorylation and stimulation of endogenous PKB activity, though with differing profiles. The addition of BDNF, or insulin resulted in a rapid and sustained phosphorylation and stimulation of PKB activity, whilst EGF stimulation, which does not promote survival, caused a more transient phosphorylation and stimulation of PKB activity. We also investigated the involvement of the PKB substrate, glycogen synthase kinase 3 (GSK 3). All three growth factors caused the inactivation of GSK-3beta, suggesting that the inactivation of GSK-3beta does not correlate with survival.     

The BDNF rs6265 variant may interact with overweight and obesity to influence obesity-related physical,metabolic and behavioural traits in Pakistani individuals

Background: The association of the variant rs6265 (G>A) in the brain-derived neurotrophic factor (BDNF) gene with obesity and other obesity-related parameters is not known for the Pakistani population. Moreover, the effects of interaction between BDNF rs6265 and overweight/obesity on obesity-related traits have never been investigated before.

Aim: To find the association of the BDNF rs6265 with obesity and related traits and to explore the effect of rs6265?×?obesity interaction on obesity-related traits in Pakistanis.

Subjects and methods: The study involved a total of 606 subjects, including 306 overweight and obese (OW/OB) cases and 300 normal weight (NW) controls. The genotyping of the BDNF rs6265 was done and obesity-related anthropometric, physical, behavioural and metabolic parameters were determined. Statistical analyses using SPSS software were performed to find the associations.

Results: The study revealed a lack of association of the BDNF rs6265 with obesity and obesity-related traits. On the other hand, the interaction between the BDNF rs6265 and overweight/obesity was found to be significantly associated with some of the obesity-related anomalous traits. However, no association between rs6265 and these anomalous traits was seen in either group when the association test was performed in NW and OW/OB groups separately.

Conclusion: The BDNF rs6265, in the presence of obesity, may be associated with elevated risk of anomalous metabolic, behavioural and physical traits and obesity-related co-morbidities, but it needs to be validated in a significantly larger Pakistani sample population.     

Association of polymorphisms in the BDNF,DRD1 and DRD3 genes with tobacco smoking in schizophrenia

Emerging evidence indicates that the DRD1‐BDNF‐DRD3 cluster plays an important role in nicotine addiction. We have performed an association analysis of 42 SNPs within these genes with cigarette consumption in a group of 341 schizophrenia patients. The ACCG haplotype consisting of four BDNF markers (Val66Met (rs6265), rs11030104, rs2049045 and rs7103411) showed an association with the risk of smoking (p = 0.0002). Both DRD1 markers tested (rs4532 and rs686) and the DRD3 marker (rs1025398) showed association with quantity of tobacco smoked (p = 0.01, 0.005 and 0.002, respectively). Our findings are preliminary; however, they support the involvement of the DRD1, BDNF and DRD3 genes in smoking behaviour.     

Transmission distortion of BDNF variants to bipolar disorder type I patients from a South American population isolate.

Recent reports have implicated polymorphisms in the brain derived neurotrophic factor (BDNF) gene region in the etiology of several psychiatric phenotypes, including bipolar disorder. Significant disease association has been reported for the G allele at SNP rs6265, which encodes for Valine at position 66 of BDNF (Val66Met), an apparently functional variant of this key BDNF. Here we examined a sample of 224 bipolar type I patients and available parents (comprising a total of 212 nuclear families) ascertained in a South American population isolate (Antioquia, Colombia). We tested for transmission distortion to bipolar patients of alleles at the rs6265 polymorphism and at a microsatellite marker 1.3 kb away from this SNP. Significant excess transmission of the rs6265 G allele to cases was observed (chi(2) = 10.77, d.f. = 1, P = 0.001). Two-locus haplotype analysis showed a significant global transmission distortion (chi(2) = 16.059, d.f. = 7, P = 0.025) with an excess transmission of a haplotype comprising the rs6265 G allele and microsatellite allele 227. These results are consistent with previous studies pointing to a role for BDNF in susceptibility to mood disorders.     

Polymorphisms of BDNF and CACNA1C are not associated with cognitive functioning in bipolar disorder or healthy controls

Introduction: The cause of cognitive dysfunction in bipolar disorder (BD) is not well understood. BDNF and CACNA1C are two susceptibility genes for the disorder that have also been reported to be associated with cognitive deficits in the disorder, but the studies have been small and with conflicting results. We therefore attempted to replicate an association between cognitive dysfunction with the most commonly studied single nucleotide polymorphisms rs6265 and rs1006737.

Methods: Regression models with five aggregated cognitive domains derived from a comprehensive test battery and IQ score were run using directly genotyped risk variants of SNPs rs6265 and rs1006737 as predictors with covariates as appropriate. Models were performed in a clinical sample of Swedish patients with BD (N?=?114) and sex- and age-matched population controls (N?=?104).

Results: No significant associations (regardless of correction for multiple testing) between the BDNF and CACNA1C risk variants and cognitive functioning were found in either patients or controls.

Conclusions: Our results do not support that the common genetic risk variants in rs6265 and rs1006737 are associated with cognitive dysfunction.     

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.     

Influence of Candidate Genes on Attention Problems in Children: A Longitudinal Study

Attention problems form one of the core characteristics of Attention-Deficit Hyperactive Disorder (ADHD), a multifactorial neurodevelopmental disorder. From twin research it is clear that genes play a considerable role in the etiology and in the stability of ADHD in childhood. Association studies have focused on genes involved in the dopaminergic and serotoninergic systems, but with inconclusive results. This study investigated the effect of 26 Single Nucleotide Polymorphisms (SNPs) in genes encoding for serotonin receptors 2A (HTR2A), Catechol-O-Methyltransferase (COMT), Tryptophane Hydroxylase type 2 (TPH2), and Brain Derived Neurotrophic Factor (BDNF). Attention problems (AP) were assessed by parental report at ages 3, 7, 10, and 12 years in more than 16,000 twin pairs. There were 1148 genotyped children with AP data. We developed a longitudinal framework to test the genetic association effect. Based on all phenotypic data, a longitudinal model was formulated with one latent factor loading on all AP measures over time. The broad heritability for the AP latent factor was 82%, and the latent factor explained around 55% of the total phenotypic variance. The association of SNPs with AP was then modeled at the level of this factor. None of the SNPs showed a significant association with AP. The lowest p-value was found for the rs6265 SNP in the BDNF gene (p = 0.035). Overall, our results suggest no evidence for a role of these genes in childhood AP.