海洛因依赖与多巴胺D2受体基因的关联分析

目的：探讨海洛因依赖与多巴胺D2受体基因的相关性。方法：应用聚合酶链反应-限制性片段长度多态性分析技术，检测302例海洛因依赖者和177名正常对照者的D2受体基因-141C Ins/Del多态性的基因型和等位基因频率。结果：共检测出三种基因型：纯合子-141C Del/Del(304bp、304bp)、杂合子-141C Ins/Del(304bp、160bp、144bp)、纯合子-141C Ins/Ins(160bp、144bp)。海洛因依赖组的-141C Ins/Del多态性的基因型频率与对照组的差异无显著性（X^2=5.33，P=0.07），但海洛因依赖组-141C Del等位基因频率（16.6％）高于对照组（11.0％；X^2=5.37，P=0.02）。结论：D2受体基因-141 Cins/Del多态性可能与海洛因依赖的易感性相关。     

Association of specific haplotypes of neurotrophic tyrosine kinase receptor 2 gene (NTRK2) with vulnerability to nicotine dependence in African-Americans and European-Americans.

BACKGROUND: The gene encoding neurotrophic tyrosine kinase receptor 2 (NTRK2) has been localized to a region on chromosome 9q22-q23 that showed a "suggestive" linkage to nicotine dependence (ND) in our previous linkage analyses. However, no association of NTRK2 with ND has been identified. METHODS: Family-based association analyses of 2037 participants (1366 African Americans [AA], 671 European Americans [EA]) representing 602 nuclear families were performed to evaluate association of nine single nucleotide polymorphisms (SNPs) within NTRK2 with ND. RESULTS: Individual SNP-based association analysis indicated that in the EA sample, SNPs rs1659400 and rs1187272 were significantly associated with at least one adjusted ND measure. Haplotype analysis revealed that even after Bonferroni correction, the haplotype T-T-A of rs1659400-rs1187272-rs1122530 had a highly significant positive association, with adjusted ND measures in the EA sample (max Z = 3.78; p = .0001, frequency 59.9%). We further identified a major haplotype, T-G-C-A-A (26%), formed by rs993315-rs736744-rs920776-rs4075274-rs729560, which showed a significant positive association (max Z = 2.97, p = .003) with adjusted ND measures in the AA sample. CONCLUSIONS: These results strongly suggest that NTRK2 is a susceptibility gene for ND. These findings imply that NTRK2 plays a role in the etiology of ND and represents an important biological candidate for further investigation.     

Mu opioid receptor gene polymorphisms and heroin dependence in Asian populations

The distribution of three polymorphisms of the mu opioid receptor gene (OPRM1) was investigated in four different Asian populations, and in heroin-dependent subjects deriving from three of these populations. For the A118G polymorphism, we found significant differences in allele and genotype frequencies between different ethnic groups and highly significant association with heroin dependence in Indians for both genotype distribution (p = 0.024) and allele frequency (p = 0.009). For the C17 T polymorphism, the minor allele was documented in Chinese and Malays for the first time. Molecular haplotyping revealed complete linkage dis-equilibrium between the A118G and C17 T polymorphisms. Linkage disequilibrium between the A118G and C1031G polymorphisms was found to be almost complete in all four ethnic groups.     

5-羟色胺2A受体基因多态与海洛因成瘾及渴求程度的关联分析

目的探讨5-HT2A-1438A／G基因多态与海洛因成瘾及线索诱发海洛因渴求程度的关系。方法采 用PCR-RFLP技术对380例海洛因依赖者(依赖组)和275名健康人(对照组)的5-HT2A-1438A／G基因多态进行检 测,并对依赖组行线索诱发海洛因渴求实验。比较依赖组和对照组的5-HT2A-1438A／G多态基因型及等位基因频 率,分析依赖组不同基因型与线索诱发海洛因渴求程度和主观戒断反应的关系。结果 (1)依赖组与对照组的5- HT2A-1438A／G的基因型和等位基因频率均无显著性差异(P>0．05)。(2)依赖组中,5-HT2A-1438A／G的3种多态 基因型诱发渴求和主观戒断反应的差异有统计学意义(P<0．05),G／G基因型诱发渴求和主观戒断反应均小于A／ A(P=0．024,P=0．009)和A／G(P=0．018,P=0．011)基因型。结论未发现5-HT2A-1438A／G基因多态与海洛 因成瘾有关,但该基因多态性与线索诱发海洛因的渴求程度有关,A+(A／A和A／G)携带者线索诱发海洛因的渴求 程度和主观戒断反应明显高于A-(G／G)携带者。     

多巴胺D2受体基因多态性与脑出血的相关性研究

目的 探讨多巴胺D2受体（DRD2）基因TaqI位点多态性与中国湖南地区汉族人群脑出血发病的相关性.方法 本研究筛选121例脑出血患者,匹配103例正常体检人群为对照,PCR-RFLP检测DRD2 TaqI基因多态性.结果 DRD2 TaqI三种基因型（A1A1,A1 A2,A2A2）频率及两种等位基因（A1,A2）频率在脑出血组和正常对照组分布的差异无统计学意义（P＞0.05）.脑出血组中高血压亚组、非高血压亚组及对照组三者两两比较DRD2 TaqI基因型频率分布的差异无统计学意义（P＞0.05）.Logistic回归调整了脑出血环境因素的影响后,DRD2 TaqI基因多态性仍与脑出血的无相关性（P＞0.05）.结论 DRD2 TaqI基因多态性可能与中国湖南地区汉族人群脑出血无关.     

The dopamine receptor D1 gene is associated with the length of interval between first heroin use and onset of dependence in Chinese Han heroin addicts

Previous researches showed that the dopamine receptor D1 (DRD1) may play a critical role in drug dependence. This research aimed to determine whether DRD1 played a role in development of heroin dependence in Chinese heroin-dependent patients. 465 Chinese Han heroin-dependent subjects and 379 healthy controls were recruited in the Shanghai region. Five single-nucleotide-polymorphisms (SNPs) of the DRD1 gene were genotyped in all subjects. The results found that the frequencies of DRD1 SNP genotypes or haplotypes were not different between heroin-dependent patients and controls. Among heroin-dependent patients, subjects with rs5326CC and/or rs6882300AA genotypes develop to heroin-dependent more rapidly than those without rs5326CC and/or rs6882300AA genotypes. The results indicated that DRD1 gene polymorphism may not play an important role in the susceptibility of heroin dependence in the Chinese Han population, but it may be associated with the rapidity of heroin dependence development from first drug use.     

Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations

The neuropeptide galanin (GAL) is widely expressed in the central nervous system. Animal studies have implicated GAL in alcohol abuse and anxiety: chronic ethanol intake increases hypothalamic GAL mRNA; high levels of stress increase GAL release in the central amygdala. The coding sequence of the galanin gene, GAL, is highly conserved and a functional polymorphism has not yet been found. The aim of our study was, for the first time, to identify GAL haplotypes and investigate associations with alcoholism and anxiety. Seven single-nucleotide polymorphisms (SNPs) spanning GAL were genotyped in 65 controls from five populations: US and Finnish Caucasians, African Americans, Plains and Southwestern Indians. A single haplotype block with little evidence of historical recombination was observed for each population. Four tag SNPs were then genotyped in DSM-III-R lifetime alcoholics and nonalcoholics from two population isolates: 514 Finnish Caucasian men and 331 Plains Indian men and women. Tridimensional Personality Questionnaire harm avoidance (HA) scores, a dimensional measure of anxiety, were obtained. There was a haplotype association with alcoholism in both the Finnish (P=0.001) and Plains Indian (P=0.004) men. The SNPs were also significantly associated. Alcoholics were divided into high and low HA groups (>or= and 相似文献   

多巴胺D3受体基因多态性与精神分裂症及其亚型的关联分析

目的：探讨精神分裂症及其亚型与多巴胺D3受体（DRD3）基因Ser9Gly多态性之间的关联。方法：使用病例－对照的关联分析方法，对528例中国汉族精神分裂症患者及241名正常对照者DRD3的多态性进行检测，并进行关联分析。结果：精神分裂症患者Gly9Gly基因型及Gly9等位基因明显高于对照组（患者组及对照组Gly9Gly基因分别为8．5％及4．6％，P＝0．053；Gly9等位基因频率分别为28．4％及23．0％，P＜0．05）；且首次发病为阳性症状者与对照组之间的等位基因的差异也有显著性（Gly9等位基因频率分别为28．6％及23．0％，P＜0．05，OR＝1．337，95％CI＝1．020－1．752）。结论：DRD3基因Ser9Gly多态性与精神分裂症整体存在显著性关联，尤其是与首次发病以阳性症状为主者关系密切。     

双相情感障碍与DRD3、DRD2和COMT基因多态性的关联分析

目的　探索多巴胺D3受体 (DRD3)、多巴胺D2受体 (DRD2 )和儿茶酚氧位甲基转移酶 (COMT)基因多态性与双相情感障碍的关系。方法　使用病例 对照的关联分析方法 ,对 10 5名双相情感障碍患者和 12 8名对照者之DRD3、DRD2和COMT的多态性进行检测 ,并进行关联分析。结果　DRD3等位基因在两组间的分布有显著性差异 (χ2 =5 77,P =0 0 2 ) ,Logistic多元回归分析发现基因型 1/ 1和 2 / 2在两组间分布的有显著性差异 (P =0 0 36 ,OR=5 72 7) ,等位基因分析也有显著性差异 (P =0 0 2 2 ,OR =6 786 ) ;DRD2和COMT基因型和等位基因的分布在两组间无显著性差异 (χ2 =1 983,P =0 37/ χ2 =1 6 7,P =0 4 1;χ2 =0 2 16 ,P >0 0 5 / χ2 =0 14 3,P >0 0 5 ) ;将DRD3和DRD2共同分析时发现OR值升高 (OR =6 6 97)。结论　DRD3基因多态性与双相情感障碍有关联 ,且与DRD2有协同作用。     

Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD.

The authors investigated the association between dopamine receptor D2, D3 gene polymorphisms, and the risk of developing motor fluctuations in PD. DRD3 BalI and MspI polymorphisms were not associated with risk of developing motor fluctuations. However, the genotypic distribution of DRD2 TaqIA polymorphism was significantly different in motor fluctuators and nonmotor fluctuators. These findings suggest that DRD2 TaqIA polymorphism may be associated with an increased risk for developing motor fluctuations in PD.     

Association of SNPs and haplotypes in GABAA receptor beta2 gene with schizophrenia

Disturbances in GABAergic system have been observed in schizophrenics. In the present study, population association analysis was performed on 19 SNPs in the alpha(1), beta(2), gamma(2), epsilon and pi subunit genes of GABA(A) receptor. Five SNPs in GABRB2, namely B2I7G1584T, rs1816071, rs194072, rs252944 and rs187269, were found to be significantly associated, and their haplotypes in linkage disequilibrium, with schizophrenia. This represents the first report on any disease association of SNPs in the human GABA(A) receptor genes, and focuses attention on the GABAergic hypothesis of schizophrenia etiology.     

Association of specific haplotypes of GAS6 gene with stroke

The product of the growth arrest-specific gene 6 (GAS6), a ligand for tyrosine kinase receptors, is a vitamin K-dependent protein, structurally related to anticoagulant protein S. Gas6-deficient mice are protected against thrombosis, demonstrating the importance of this protein in the cardiovascular system. In a preliminary study on GAS6 polymorphisms and atherothrombotic disease we found an association between the AA genotype of the c.834 + 7G > A GAS6 polymorphism and stroke. In order to further explore this association by considering GAS6 haplotypes and the main stroke subtypes, 457 patients with ischemic stroke, 199 with hemorrhagic stroke and 150 asymptomatic controls were genotyped for eight GAS6 polymorphisms and other genetic markers in the same genome region. Association was measured by logistic regression analysis. The THESIAS program was used to measure linkage disequilibrium and haplotype frequencies. In univariate analysis, the GAS6 c.834 + 7AA genotype was found associated with decreased risk for stroke (OR: 0.59; 95%CI: 0.37-0.93). After adjustment for vascular risk factors, association was maintained when stroke subtypes affecting the microvasculature such as lacunar stroke and deep haemorrhage, were grouped together (OR: 0.44; 95%CI: 0.21-0.90). Furthermore, haplotype analysis revealed that association was even stronger when the c.834 + 7A allele was present in a specific haplotype (CACA) of four GAS6 polymorphisms. From these results we conclude that the A allele of the GAS6 c.834 + 7G > A polymorphism and more specifically, the CACA haplotype, is less prevalent in patients with stroke, suggesting a protective role for stroke of this haplotype.     

Association of short-term response to haloperidol treatment with a polymorphism in the dopamine D(2) receptor gene

OBJECTIVE: Pharmacogenetic influences on therapeutic response to neuroleptic treatment are poorly understood. This study investigates the association of response to short-term haloperidol treatment with a Taq I polymorphism in the DRD2 gene. METHOD: Fifty-seven patients with acute psychosis were treated with haloperidol for up to 28 days. Improvement and response were measured by using the Positive and Negative Syndrome SCALE: Forty-one patients were homozygous for allele 2, and 16 were heterozygous. RESULTS: Heterozygous patients showed a greater improvement in positive, but not in negative, symptoms on all treatment days than patients homozygous for allele 2. Differences in improvement of positive symptoms reached statistical significance on days 14, 21, and 28. On treatment day 14, 10 (62.5%) of 16 heterozygous patients had at least 50% improvement of positive symptoms, compared with 11 (28.9%) of 38 homozygous patients. CONCLUSIONS: These results support the hypothesis that genetic variations in the DRD2 gene may influence the individual response to antipsychotics.     

儿茶酚胺甲基氧位转移酶(COMT)基因多态与海洛因依赖的关联分析

目的 探讨儿茶酚胺甲基氧位转移酶(COMT)基因多态性与海洛因依赖的相关性.方法 采用TagMan探针SNP基因分型技术对507例海洛因依赖者(患者组)和487名健康者(对照组)的COMT基因上7个单核苷酸多态(SNP)位点(rs737866,rs933271,rs l 544325,r84818,rs4680,rs 174696,rs 174699)进行基因分型和关联分析.结果 COMT基因rs737866,rs933271两位点基因型在病例对照组中存在差异(P=0.047,P=0.011),其等位基因C与海洛因依赖相关(P=0.017,P=0.048).由rs737866-rs933271-rsl544325构建的CTG单倍体型在海洛因依赖者中比例较高.结论 rs737866位点携带C等位基因者具有较高的海洛因依赖易感性.     

多巴胺D2受体基因rs1800497多态性与精神分裂症的关联分析

目的 探讨中国汉族人群多巴胺D2受体（DRD2）基因rs1800497多态性与精神分裂症发病的关系及其与性别的关联性.方法 采用TaqMan法检测200例精神分裂症患者（患者组）和219名健康对照（对照组）DRD2基因rs1800497单核苷酸多态性（SNP）,并对等位基因、基因型频率进行比较.结果 患者组与对照组rs1800497等位基因分布和基因型分布差异均无统计学意义（P＞0.05）.患者组或对照组不同性别rs1800497等位基因分布和基因型分布差异均无统计学意义（P＞0.05）.男性患者组与对照组相比或女性患者组与对照组相比,rs1800497等位基因分布和基因型分布差异均无统计学意义（P＞0.05）.结论 中国汉族人群DRD2 rs1800497位点可能不是精神分裂症的易感位点.     

Cellular colocalization of dopamine D1 mRNA and D2 receptor in rat brain using a D2 dopamine receptor specific polyclonal antibody

1. The main objective of this work was to investigate the extent of cellular colocalization of dopamine D1 and D2 receptors in the rat brain. A double labeling technique, that combined immunocytochemical labeling of the D2 receptor using polyclonal antibodies raised against the third intracellular loop of the short isoform of the human D2 receptor in combination with in situ hybridization detecting D1 mRNA expression, was designed to accomplish this goal. 2. The specificity of the antisera obtained was confirmed by immunoprecipitation assay, Western blot analysis, and immunocytochemistry on D2R transfected cells and murine brain tissue. Western blot using the D2 receptor antibody revealed a specific broad band centered at 67 kDa in transfected cells and a major protein of 88 kDa corresponding to D2R expressed in the caudate-putamen, to a lesser extent in the cortex, and not at all detected in the hypothalamic region. 3. The content of neurons double-labeled for D1/D2 receptors was observed at in differing intensities in the dorsal endopiroform nucleus, the intercalated nucleus of amygdala, the anterior part of the cortical nucleus amygdala, the nucleus of the lateral olfactory tract, the piriform cortex, the parabrachial nucleus, the supraoptic nucleus and the parabigeminal nucleus. All other regions of the brain revealed neurons expressing either D1 or D2 dopamine receptors but not both at that same time. 4. These results clearly demonstrated that specific neurons expressed both receptors D1 and D2, and that this colocalization was restricted to particular regions of the rat brain.     

Association between a promoter polymorphism in the dopamine D2 receptor gene and schizophrenia.

Genetic factors and dopamine receptor dysfunction have been implicated in the pathophysiology of schizophrenia. Recently, an association between a putative functional promoter polymorphism (-141C Ins/Del) in the dopamine D2 receptor gene and schizophrenia was reported. We investigated unrelated Swedish schizophrenic patients (n = 129) and control subjects (n = 179) for the same polymorphism. Similarly to a previous Japanese report, the - 141C Del allele frequency was significantly lower in patients than controls (chi2=4.4, 1 df, p<0.05; odds ratio 0.49, 95% confidence interval 0.26-0.91). The present and previous results may indicate that the -141C Ins/Del dopamine D2 receptor gene polymorphism affects susceptibility to schizophrenia.     

多巴胺D3受体基因多态性与精神分裂症初发期患者抗精神病药疗效关系的研究

目的　探讨多巴胺D3 受体 (DRD3)基因多态性与精神分裂症初发期患者精神症状严重度和抗精神病药疗效是否相关。方法　对 10 9例精神分裂症初发期患者分别进行利培酮治疗 [4 3例 ,3～ 5mg/d ,平均 ( 4 0± 0 5 )mg/d]和氯丙嗪治疗 [6 6例 ,15 0～ 6 0 0mg/d ,平均 ( 339± 87)mg/d],疗程 10周。采用聚合酶链反应 限制性片段长度多态性技术检测其中 10 8例患者 (男 5 2例 ,女 5 6例 )DRD3基因ser9gly多态性。采用阳性和阴性症状量表 (PANSS)评定患者治疗前和治疗第 10周末的精神症状 ,并分析基因型及其他临床指标与PANSS分值和减分率的关系。结果　DRD3ser9gly基因型在各患者组分布频率均符合Hardy Weinberg定律 (P >0 0 5 ) ;基因型在治疗显效和未显著进步组分布频率的差异有显著性 ( χ2 =6 4 4 ,ν=2 ,P <0 0 5 ) ;各基因型亚组临床指标的差异均无显著性 (均P >0 0 5 ) ;基因型与患者治疗前PANSS总分及治疗第 10周末PANSS总减分率、阳性症状减分率的差异均有显著性(均P <0 0 5 )。结论　DRD3基因ser9gly功能多态性可能是精神分裂症初发期患者精神症状严重程度和抗精神病药疗效 (尤其对阳性症状疗效 )的遗传影响因子。