去甲肾上腺素转运体基因多态性与中国南方汉族人群重性抑郁症的关联研究

目的:探讨去甲肾上腺素转运体(NET)基因多态性与中国南方汉族人群中重性抑郁症患者之间的关系。方法:采用高温连接酶检测反应法,检测254例抑郁症患者和231例正常对照者的NET基因rs5569位点基因型和等位基因分布。结果:①NET基因rs5569位点基因型和等位基因频率在患者组和对照组的分布差异无统计学意义。②携带rs5569TT基因型患者的汉密尔顿抑郁量表(HAMD)睡眠障碍分值显著高于携带CC、CT基因型患者。携带rs5569CC基因型患者的汉密尔顿焦虑量表(HAMA)精神性焦虑因子分值显著低于TT、CT基因型患者。结论:未发现中国南方汉族人群NET基因rs5569多态性与重性抑郁症存在关联但NET基因rs5569多态性可能与症状群中睡眠障碍和精神性焦虑有关联。     

5-羟色胺转运蛋白基因多态性与精神分裂症的传递不平衡分析

目的 探讨5—羟色胺转运蛋白基因第2内含子可变数目串联重复序列(Intronic，variable number tandem repeat，Intronic VNTR)位点和启动子区VNTR位点(5—HTTLPR)在精神分裂症发病机理中的作用。方法 应用传递不平衡分析方法对来自上海、西安和吉林的总计314个精神分裂症简单核心家庭进行分析。结果 三地单独及合并样本的传递不平衡分析结果表明，这两个多态位点由杂合子父母传递给患病子女的等位基因频率差异无显著性。结论 5—羟色胺转运蛋白基因上Intronic VNTR和5—HTTLPR多态位点在中国汉族人群精神分裂症发病机理中不起主要作用。     

去甲肾上腺转运蛋白基因多态性与高血压合并心力衰竭的关系

目的探索汉族人群去甲肾上腺转运蛋白(norepinephrine transporter,NET)基因(SLC6A2)启动子3、2多态性与高血压病(essential hypertension,EH)合并心力衰竭(heart failure,HF)的关系。方法按年龄、性别和居住地配对原则收集3组受试者:对照组(n=176,健康体检者),EH组(n=176,心功能正常的EH患者)和EH-HF组(n=176,EH合并NYHAⅢ～Ⅳ级心功能患者),应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)检测SLC6A2启动子3和启动子2多态性。结果EH-HF组SLC6A2启动子3AG/GG基因型分布频率(41.48%)高于EH组(26.70%)和对照组(22.16%),3组SLC6A2启动子2GG、GC和CC基因型分布差异无统计学意义。以EH组为参照系,调整混杂因素后,SLC6A2启动子3AG/GG基因型发生心衰的OR值为1.905(95%CI:1.138～3.188,P=0.014);以SLC6A2启动子3A-G/启动子2单倍体为参比基线,单因素分析SLC6A2启动子3G-C/启动子2单倍体发生心衰的OR值为2.744(95%CI:1.390～5.417,P=0.004),而且携带SLC6A2启动子3AG/GG基因型的EH-HF患者血浆脑钠肽水平明显高于AA基因型患者(P<0.001)。结论携带SLC6A2启动子3G等位基因及启动子3G-C/启动子2单倍体型患者与EH-HF有关,可能是EH-HF分子遗传学基础之一。     

长期压力超负荷心力衰竭时心脏交感神经去甲肾上腺素转运蛋白表达变化的意义

目的： 观察长期压力超负荷模型大鼠心力衰竭（HF）时心脏交感神经去甲肾上腺素转运蛋白（NET）mRNA及蛋白水平表达变化。 方法：成年雄性Wistar大鼠随机分为：HF组和假手术组。采用腹主动脉缩窄术建立大鼠心脏压力超负荷HF模型。用免疫组织化学、Western blotting、实时荧光定量PCR技术检测NET表达。 结果：腹主动脉缩窄8周后， HF组大鼠心脏NET mRNA及蛋白表达均低于假手术组（P<0.01）。 结论：长期心脏压力超负荷导致心力衰竭时NET mRNA及蛋白表达均降低，NET mRNA表达下降可能是导致NET蛋白水平下降的重要原因，提示NET表达异常可能是HF时心脏交感神经功能异常的基础。     

递增负荷运动大鼠脑皮质神经元和脑脊液中去甲肾上腺素、5-羟色胺的动态变化

背景：运动性疲劳的发生、恢复是否与脑脊液循环存在着某种联系？ 目的：观察递增负荷运动后大鼠大脑皮质和脑脊液中去甲肾上腺素、5-羟色胺的动态变化及其相关性。 方法：随机将30只雄性SD大鼠分为对照组10只,运动组20只,运动组采用6周递增负荷运动方案训练,游泳时间由第1周的10 min递增为第6周的60 min,负重由体质量的3%增至体质量的5%。对照组正常饲养。 结果与结论：高效液相色谱检测结果显示,递增负荷运动后即刻,大鼠大脑皮质和脑脊液中去甲肾上腺素、5-羟色胺的水平显著增高;递增负荷运动后24 h,大鼠大脑皮质中去甲肾上腺素、5-羟色胺水平继续增高(P < 0.01),而脑脊液中去甲肾上腺素、5-羟色胺降至正常水平。其中,递增负荷运动后即刻,大鼠大脑皮质中的去甲肾上腺素与5-羟色胺水平及呈显著正相关(P < 0.05),大脑皮质和脑脊液中的去甲肾上腺素及5-羟色胺水平高度相关(P < 0.01)。提示递增负荷运动后去甲肾上腺素的兴奋作用和5-羟色胺的抑制作用处于动态平衡中。递增负荷运动后的即刻,脑脊液中去甲肾上腺素、5-羟色胺的变化能够反映大脑皮质中去甲肾上腺素、5-羟色胺的变化。     

5-羟色胺转运体基因多态性与支气管哮喘及抑郁症易感性的研究

目的 检测5-羟色胺转运体(5-hydroxytryptamine transporter,5-HTT)基因的两种多态性(5-HTTLPR及Stin2),以探讨哮喘合并抑郁症的分子遗传学机制.方法 收集成人哮喘患者156例,采用汉密尔顿抑郁量表(Hamilton depression scale,HAMD)进行抑郁评分,将哮喘组分为哮喘合并抑郁组(HAMD≥8分)和单纯哮喘组(HAMD<8分).另设立两组对照,即抑郁症组(n=508)和健康对照组(n=433).采集所有受试者外周血,应用聚合酶链反应方法,扩增包括5-HTTLPR或Stin2多态区域的5-HTT基因片段,在琼脂糖凝胶电泳后使用全自动凝胶数码成像及分析系统分析扩增目的 基因片段.结果 Stin2多态性的基因型频率分布和等位基因频率分布显示,具有Stin2.12/Stin2.10基因型或Stin2.10等位基因型的男性发生哮喘的风险明显增加(Stin2.12/Stin2.10:OR=2.291,95%CI:1.195,4.390;Stin2.10:OR=1.942,95%CI:1.069-3.527),而5-HTTLPR的基因型和等位基因频率分布在哮喘(包括哮喘合并抑郁组和单纯哮喘组)或按性别分层的哮喘与健康对照之间的差异均无统计学意义(P均>0.05).结论 5-HTT基因Stin2多态位点可能在男性哮喘发病中发挥一定作用,该结果支持哮喘与抑郁之间可能存在一定遗传学发病机制相关性的假设.     

clock基因rs1801260多态性与抑郁症的关联分析

目的:探讨clock基因与汉族人群抑郁症的关联。方法:用Snapshot SNP分型技术对155例抑郁症患者(其中包括133名抑郁症睡眠障碍者)和150名正常对照进行clock基因rs1801260位点分型,比较两组该基因多态性基因型和等位基因频率的差异。结果:与对照组相比,患者组rs1801260多态性的基因型和等位基因的频率差异无统计学意义(P0.05);对rs1801260多态性二种基因型C/T、T/T抑郁症的临床资料比较,显示HAMA总分差异具有统计学意义(t=2.012,P=0.047),其他各项没有明显差异(P0.05)。结论:clock基因rs1801260多态性可能与中国汉族抑郁症的发病无关联,但与抑郁症的焦虑程度可能关联。     

5-羟色胺转运蛋白基因多态性与脑卒中后抑郁的关联

目的:探讨5-羟色胺转运体连锁启动区(5-hydroxytryptamine transporter linked promoter region,5-HTTLPR)基因多态性与脑卒中后抑郁发病、自杀行为是否相关。方法:应用聚合酶链反应(PCR)扩增技术测定中国汉族脑卒中抑郁(poststroke depression,PSD)患者90例(PSD组)和无抑郁脑卒中患者90例(非PSD组)的5-HTTLPR基因型及等位基因,分别验证各种基因型与脑卒中抑郁症发病及自杀行为的相关性。结果:PSD组SS基因型及S等位基因频率(64.4%,75.6%)明显高于非PSD组(38.9%,58.3%),S等位基因携带者PSD患病率为LL型纯合子的1.29倍(OR=1.29,P<0.001,95%CI:1.11～1.50);对PSD组自杀行为分层比较,有自杀行为组SS基因型及S等位基因频率(76.8%,75.6%)明显高于无自杀行为组(44.1%,58.3%),PSD患者中,S等位基因携带者自杀行为发生概率为LL纯合子的1.3倍(OR=1.3,P<0.01,95%CI:1.08～1.6)。结论:5-HTTLPR基因可能是PSD的易感基因,S等位基因可能与PSD及自杀行为相关。     

体力运动和心理应激对大鼠海马去甲肾上腺素和五-羟色胺水平的影响

目的：研究长期体力运动和慢性心理应激对大鼠中枢海马去甲肾上腺素(norepinephrine，NE)和五-羟色胺(serotonin，5-HT)水平的影响，并进一步探讨这2种神经递质在运动减缓应激性海马损伤效应中的作用。方法：采用了4周自愿跑轮运动(运动组)、3周束缚应激（应激组）和预先进行4周运动再施3周应激（运动-应激组）的实验动物模型，高效液相电化学法检测实验大鼠海马的NE和5-HT水平。结果：长期运动大鼠海马的NE和5-HT水平明显升高(P<0.01)，慢性应激大鼠的5-HT水平明显降低（P<0.05）；并且，先运动再应激组的海马NE水平维持正常并显著高于单纯应激组（P<0.01），而以上2组的5-HT水平并无显著差异，且均低于单纯运动组（P<0.05）。结论：在运动益于海马的正性作用中，NE和5-HT可能是重要的调控因素；在应激损伤海马的负性作用中，5-HT可能是重要的调控因素；而在运动减缓应激性海马损伤的作用途径中，NE可能是更重要的调控因素；并且，海马NE可能对运动更敏感，而5-HT可能对应激更敏感。     

5-羟色胺1A受体基因-1019C/G多态性与自杀行为关联的meta分析

目的:采用meta分析方法评价5-羟色胺1A受体(5-HTR1A)基因多态性与自杀行为相关的研究。方法:通过计算机检索Pub Med、Embase、Web of Science、中国生物医学文献数据库(CBM)、万方、维普、知网(CNKI)等中英文数据库,严格按照制定的纳入与排除标准,选择5-HTR1A基因多态性与自杀行为相关病例对照研究,检索范围为2003年12月30日-2013年12月30日。采用STATA12.0软件进行meta分析,计算优势比(OR)及其95%可信区间(95%CI),分析5-HTR1A基因多态性与自杀行为的关联性。结果:共纳入8项研究,包括1357例有自杀行为的患者及1675例正常对照。meta分析结果表明,5-HTR1A基因CG(-1019)多态性与自杀行为的相关有统计学意义(等位基因模型,OR=0.65,95%CI:0.46~0.92,P=0.015;显性基因模型,OR=0.76,95%CI:0.64~0.91,P=0.002)。根据种族进行亚组分析发现,在亚洲人群中5-HTR1A基因单核苷酸-1019 C/G多态性与自杀行为有显著关联(等位基因模型:OR=0.48,95%CI:0.25~0.93,P=0.029;显性基因模型:OR=0.37,95%CI:0.24~0.56,P0.001);而在高加索人群中5-HTR1A基因多态性与自杀行为无显著关联(等位基因模型:OR=0.71,95%CI:0.49~1.02,P=0.065;显性基因模型:OR=0.89,95%CI:0.73~1.08,P=0.247)。结论:本meta分析的结果提示5-HTR1A基因多态性与自杀行为的发生有关,其基因多态性可能是人们产生自杀行为的一个潜在危险因素。     

Combination of the serotonin transporter and norepinephrine transporter gene promoter polymorphisms might influence harm avoidance and novelty seeking in healthy females

It has been demonstrated that the interaction between serotonin transporter (5HTT) and norepinephrine transporter (NET) functions affects each transporter function and behavior in studies using knockout mice model. In the present study, we examined the effects of the 5HTT and NET gene promoter polymorphisms on personality traits in 575 Japanese healthy subjects. The 5HTT (long/short, L/S) and NET (-3081 A/T) genotypes were identified by PCR methods, and personality traits were assessed by the Temperament and Character Inventory (TCI). Neither of the two polymorphisms affected any TCI dimension, but the interaction between them had significant effects on harm avoidance and novelty seeking in females. Subsequent analyses showed that the females with the combination of the SS genotype reducing 5HTT function and the TT genotype reducing NET function had higher harm avoidance and lower novelty seeking. The present study suggests that the combination of 5HTT and NET polymorphisms influences harm avoidance and novelty seeking in females.     

No association between serotonin transporter gene polymorphisms and personality traits

Human family and twin studies have established considerable heritable components in personality traits as assessed by self-report questionnaires. Recently, an association between a functional polymorphism in the upstream regulatory region of the serotonin transporter gene and neuroticism-related personality traits was reported. Two different serotonin transporter polymorphisms including the previously associated variant were genotyped in two samples of healthy Swedish subjects (n = 127 and n = 178, respectively) assessed with the Karolinska Scales of Personality (KSP) inventory. No statistically significant association between serotonin transporter polymorphisms and any of the eight neuroticism-related KSP scales was found. Thus, the previously reported association between serotonin transporter alleles and neuroticism-related personality traits could not be replicated in the present study. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:430–436, 1999. © 1999 Wiley-Liss, Inc.     

Association of verbal and figural creative achievement with polymorphism in the human serotonin transporter gene

The purpose of this study was to examine the potential association between the S (short) and L (long) alleles of the 5-HTTLPR polymorphism of the serotonin transporter (5-HTT) gene and verbal and figural creative ability. Sixty-two unrelated Caucasian university students (29 men and 33 women) participated in the experiment. The results showed a significant association between verbal and figural creativity scores and the 5-HTTLPR polymorphism. The subjects with S/S and L/S genotypes demonstrated higher verbal creativity scores in comparison with the L/L genotype carriers. The carriers of S/S genotype demonstrated also higher figural creativity scores in comparison with the carries of L/S and L/L genotypes. Thus, it is the first report on a significant association between the 5-HTTLPR polymorphism and creative achievements. As the 5-HTTLPR polymorphism is associated with genetically defined alteration in the brain serotonergic neurotransmission our result provides an evidence of the involvement of the central serotonin system in creativity regulation.     

Cocaine-conditioned locomotion in dopamine transporter,norepinephrine transporter and 5-HT transporter knockout mice

The behavioral effects of cocaine are affected by gene knockout (KO) of the dopamine transporter (DAT), the serotonin transporter (SERT) and the norepinephrine transporter (NET). The relative involvement of each of these transporters varies depending on the particular behavioral response to cocaine considered, as well as on other factors such as genetic background of the subjects. Interestingly, the effects of these gene knockouts on cocaine-induced locomotion are quite different from those on reward assessed in the conditioned place preference paradigm. To further explore the role of these genes in the rewarding effects of cocaine, the ability of five daily injections of cocaine to induce conditioned locomotion was assessed in DAT, SERT and NET KO mice. Cocaine increased locomotor activity acutely during the initial conditioning session in SERT KO and NET KO, but not DAT KO, mice. Surprisingly, locomotor responses in the cocaine-paired subjects diminished over the five conditioning sessions in SERT KO mice, while locomotor responses increased in DAT KO mice, despite the fact that they did not demonstrate any initial locomotor responses to cocaine. Cocaine-induced locomotion was unchanged over the course of conditioning in NET KO mice. In the post-conditioning assessment, conditioned locomotion was not observed in DAT KO mice, and was reduced in SERT KO and NET KO mice. These data reaffirm the central role of dopamine and DAT in the behavioral effects of cocaine. Furthermore, they emphasize the polygenic basis of cocaine-mediated behavior and the non-unitary nature of drug reward mechanisms, particularly in the context of previous studies that have shown normal cocaine-conditioned place preference in DAT KO mice.     

shRNA干扰蓝斑核去甲肾上腺素转运体(NET)表达对大鼠抑郁样行为的改善作用

目的:探讨利用慢病毒在蓝斑核(locus coeruleus,LC)敲除去甲肾上腺素转运体(norepinephrine transporter,NET)对大鼠抑郁样行为的影响。方法:构建NET-shRNA慢病毒载体及阴性对照序列,感染PC12细胞后通过Q-PCR和Western Blot方法测定NET mRNA和蛋白水平;建立慢性不可预见性温和应激大鼠抑郁症模型,双侧蓝斑核注射NET-shRNA;3周后采用强迫游泳实验、糖水偏好实验、旷场实验检测大鼠抑郁样行为;Western Blot检测大鼠NET水平;高效液相色谱法(HPLC)检测大鼠去甲肾上腺素(norepinephrine,NE)水平。结果:Q-PCR和Western Blot检测结果显示:shRNA-1146沉默效率最高(P0.01);与抑郁症模型组相比,蓝斑核注射NET-shRNA组大鼠强迫游泳不动时间减少、糖水偏好率增加、旷场实验得分增加(P0.01),蓝斑核NET表达下降(P0.01)、NE水平升高(P0.05)。结论:NET-shRNA慢病毒注射蓝斑核能下调NET的表达,改善大鼠抑郁样行为,为抑郁症的基因治疗提供了实验依据。     

Association of the serotonin transporter gene, neuroticism and smoking behaviours

Cigarette consumption and smoking cessation are influenced in part by genes. Personality traits have also been implicated in the aetiology of smoking. Neuroticism, a personality trait with a heritable component, correlates well with anxiety and depression, increasing the risk of being a smoker and decreasing the chance of smoking cessation. Several prior studies in non-British populations have given conflicting results as to whether some genetic polymorphisms affect the relationship between smoking and neuroticism. This study investigated the influence of serotonin transporter (5HTTLPR) genotypes on a composite measure of neuroticism and cigarette consumption/smoking cessation in a British population. Although neuroticism was significantly associated with cigarette consumption and smoking cessation, genotype did not affect this relationship. Our results do not support initial interest in utilising 5HTTLPR genotypes in combination with neuroticism ratings for predicting outcome in smoking cessation clinical settings.     

Depression with psychotic features is influenced by the polymorphism of the serotonin transporter gene

Introduction

Current diagnostic classifications regard psychotic symptoms during depressive episodes as indicators of depression severity. However, growing evidence suggests that depression with psychotic symptoms (MDP) may represent a distinct subtype of depression. In the course of the search for discriminating factors we tested the hypothesis that the serotonin transporter gene (5-HTTLPR) may interact with the manifestation of psychotic symptoms in acute depression.

Methods

112 inpatients (61 female) with a depressive episode (16 bipolar, 86 unipolar) at admission were genotyped for 5-HTTLPR variants. Psychotic symptoms und general psychopathology were evaluated comprehensively using the Manual of the Association for Methodology and Documentation in Psychiatry (Arbeitsgemeinschaft für Methodik und Dokumentation in der Psychiatrie, 1981). For statistical analysis a chi-square test and a logistic regression model was used.

Results

16 (14.3%) out of 112 patients were currently presenting with psychotic symptoms. The primary finding of our study was the higher prevalence of the s-allele of the 5-HTTLPR within the group of MDP patients (Pearson χ²=7.87; df=2; p<0.03). Secondly, in a logistic regression model, 5-HTTLPR was found to significantly contribute to the diagnosis of MDP (χ²=6.5; df=1; p=0.01). This effect was even more pronounced upon comparing only severely depressed patients with MDP patients. From a psychopathological perspective, MDP patients showed higher AMDP hostility and apathy scores but equal AMDP depression scores.

Discussion

This is the first study to show an influence of 5-HTTLPR on psychotic symptoms in acutely depressed patients.

Limitations

The lack of a control group and the relatively small sample size limits the present study's findings, thus replication in a larger sample is necessary.