Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients

BackgroundTherapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients.MethodsOne hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA (rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone givenasmonotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2.ResultsThe three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment.ConclusionsThe present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients.     

Alcohol withdrawal syndrome: how to predict, prevent, diagnose and treat it

(1) When people who are physically dependent on alcohol stop drinking, they experience an alcohol withdrawal syndrome. The symptoms generally resolve spontaneously within a week, but more severe forms may be associated with generalised seizures, hallucinations and delirium tremens, which can be fatal. (2) We carried out a literature review in order to obtain answers to the following questions: how to predict or rapidly diagnose a severe alcohol withdrawal syndrome; how to prevent and treat this syndrome; how to manage severe forms; and how to deal with the risk of vitamin B1 deficiency. (3) The main risk factors for severe withdrawal syndrome are: chronic heavy drinking; a history of generalised seizures; and a history of delirium tremens. (4) Anxiety, agitation, tremor, excessive sweating, altered consciousness and hallucinations are signs of a severe withdrawal syndrome. (5) Individual support and effective communication seem to reduce the risk of severe withdrawal syndrome. (6) Oral benzodiazepines are the best-assessed drugs for preventing a severe alcohol withdrawal syndrome, particularly the risk of seizures. When given for a maximum of 7 days, the adverse effects are usually mild. (7) Clinical trials of other antiepileptics suggest they are less effective than benzodiazepines, and their addition to benzodiazepine therapy offers no tangible advantage. (8) Betablockers increase the risk of hallucinations, and clonidine increases the risk of nightmares, and the efficacy of these two drugs is not well documented. Neuroleptics increase the risk of seizures. There are no convincing data to support the use of magnesium sulphate or meprobamate (the latter carries a risk of serious adverse effects). Acamprosate, naltrexone and disulfiram are not beneficial in alcohol withdrawal. (9) Gradual withdrawal, i.e. ingestion of decreasing amounts of alcohol, has not been compared with other methods but is generally not recommended. (10) There are no specific recommendations on hydration. Note that excessive water-sodium intake carries a risk of pulmonary oedema in patients with heart disease. (11) As vitamin B1 deficiency is frequent and can lead to serious complications in alcohol-dependent patients, oral vitamin B1 supplementation is widely recommended, despite the absence of comparative trials. High doses must be used to compensate for poor absorption. Intravenous administration is best if patients have very poor nutritional status or severe complications such as Gayet-Wernicke encephalopathy (a medical emergency), even though rare anaphylactic reactions have been reported after vitamin B1 injection. (12) Planned alcohol withdrawal in specialised hospital units has been extensively studied. Outpatient withdrawal may be more appropriate for patients who are at low risk of developing severe withdrawal syndrome. (13) A large proportion of alcohol-dependent patients were excluded from trials of withdrawal strategies. These include elderly patients, patients with serious psychiatric or somatic disorders, and patients who are also dependent on other substances. (14) An oral benzodiazepine is the best-assessed treatment for a single episode of generalised seizures or hallucinations during alcohol withdrawal. (15) In randomised comparative trials benzodiazepines were more effective than neuroleptics in preventing delirium-related mortality. Currently, with appropriate fluid-electrolyte support, continuous monitoring of vital signs, and respiratory support if necessary, the mortality rate for delirium tremens is under 3%. (16) In practice, patients who are attempting to stop drinking alcohol need close personal support and communication, and a reassuring environment, as well as regular monitoring for early signs of a withdrawal syndrome; the latter may require benzodiazepine therapy.     

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

Alcohol withdrawal is associated with hypothalamic–pituitary–adrenal (HPA) axis dysfunction. The FKBP5 gene codes for a co-chaperone, FK506-binding protein 5, that exerts negative feedback on HPA axis function. This study aimed to examine the effects of single-nucleotide polymorphisms (SNPs) of the FKBP5 gene in humans and the effect of Fkbp5 gene deletion in mice on alcohol withdrawal severity. We genotyped six FKBP5 SNPs (rs3800373, rs9296158, rs3777747, rs9380524, rs1360780, and rs9470080) in 399 alcohol-dependent inpatients with alcohol consumption 48 h before admission and recorded scores from the Clinical Institute Withdrawal Assessment-Alcohol revised (CIWA-Ar). Fkbp5 gene knockout (KO) and wild-type (WT) mice were assessed for alcohol withdrawal using handling-induced convulsions (HICs) following both acute and chronic alcohol exposure. We found the minor alleles of rs3800373 (G), rs9296158 (A), rs1360780 (T), and rs9470080 (T) were significantly associated with lower CIWA-Ar scores whereas the minor alleles of rs3777747 (G) and rs9380524 (A) were associated with higher scores. The haplotype-based analyses also showed an association with alcohol withdrawal severity. Fkbp5 KO mice showed significantly greater HICs during withdrawal from chronic alcohol exposure compared with WT controls. This study is the first to show a genetic effect of FKBP5 on the severity of alcohol withdrawal syndrome. In mice, the absence of the Fkbp5 gene enhances sensitivity to alcohol withdrawal. We suggest that FKBP5 variants may trigger different adaptive changes in HPA axis regulation during alcohol withdrawal with concomitant effects on withdrawal severity.     

Population-Based Case-Control Study of DRD2 Gene Polymorphisms and Alcoholism

ABSTRACT

Several independent lines of evidence for genetic contributions to vulnerability to alcoholism exist. Dopamine is thought to play a major role in the mechanism of reward and reinforcement in response to alcohol. D2 dopamine receptor (DRD2) gene has been among the stronger candidate genes implicated in alcoholism. In this study, alcohol use was assessed in 196 randomly selected Kota individuals of Nilgiri Hills, South India. Six DRD2 SNPs were assessed in 81 individuals with alcoholism and 151 controls to evaluate the association between single nucleotide polymorphisms (SNPs) and alcoholism. Of the three models (dominant, recessive, and additive) tested for association between alcoholism and DRD2 SNPs, only the additive model shows association for three loci (rs1116313, TaqID, and rs2734835). Of six studied polymorphisms, five are in strong linkage disequilibrium forming onesingle haplotype block. Though the global haplotype analysis with these five SNPs was not significant, haplotype analysis using all six SNPs yielded a global P value of .033, even after adjusting for age. These findings support the importance of dopamine receptor gene polymorphisms in alcoholism. Further studies to replicate these findings in different populations are needed to confirm these results.     

Complications of alcohol withdrawal: pathophysiological insights

Disease processes or events that accompany acute alcohol withdrawal (AW) can cause significant illness and death. Some patients experience seizures, which may increase in severity with subsequent AW episodes. Another potential AW complication is delirium tremens, characterized by hallucinations, mental confusion, and disorientation. Cognitive impairment and delirium may lead to a chronic memory disorder (i.e., Wernicke-Korsakoff syndrome). Psychiatric problems associated with withdrawal include anxiety, depression, and sleep disturbance. In addition, alterations in physiology, mood, and behavior may persist after acute withdrawal has subsided, motivating relapse to heavy drinking. Recent advances in neurobiology may support the development of improved medications to decrease the risk of AW complications and support long-term sobriety.     

The treatment of alcohol withdrawal

Abrupt cessation of regular use of alcohol in a dependent person causes a withdrawal syndrome that may range from mild to extremely severe. Most patients require pharmacologic intervention, especially those with severe symptoms. Historically, the pharmacotherapy of alcohol withdrawal has involved a wide variety of agents. Benzodiazepines are currently preferred due to their consistently high degree of efficacy and laudable record of safety. In addition, beta blockers and clonidine are useful, as both effectively combat the hypertension and tachycardia commonly associated with withdrawal. They are ineffective as anticonvulsants; however. Opinions differ concerning the best treatment for withdrawal seizures. Prophylaxis with benzodiazepines may be all that is required, although some authors advocate the use of phenytoin for 5 days, especially in persons with a history of prior seizures during alcohol withdrawal. Once established, delirium tremens are difficult to treat. Benzodiazepines are most commonly used to provide sedation, and extremely large doses may be required. Careful clinical assessment is essential to the proper treatment of patients undergoing alcohol withdrawal since the coexistence of medical problems may complicate the condition.     

细胞色素P450酶1A2、2D6与多巴胺D2受体基因多态性对奥氮平治疗精神分裂症PANSS减分率的影响

目的 研究细胞色素P450酶（cytochrome P450,CYP）1A2、2D6以及多巴胺D2受体（dopamine receptor D2,DRD2）的基因多态性对奥氮平治疗精神分裂症阳性和阴性症状量表（positive and negative syndrome scale,PANSS）减分率的影响及其程度。方法 入组只用奥氮平治疗的精神分裂症住院患者178例,评定治疗前以及治疗4周后的PANSS量表得分,计算减分率。同时,收集血液,测定CYP1A2*1F、CYP2D6*10、DRD2-141C Ins/Del、DRD2-241 A>G、DRD2 Taq1A位点的基因多态性。通过方差分析,比较各基因型PANSS减分率的差异;通过多元线性回归分析,得出减分率的回归方程,并计算决定系数。结果 PANSS减分率在CYP1A2*1F（CC：65.68±11.22;CA：55.59±15.40;AA：43.75±15.20）、CYP2D6*10（CC：44.36±16.67;CT：51.78±17.81;TT：56.14±17.13）、DRD2-141C Ins/Del （Ins/Ins：55.11±17.39;Ins/Del：39.16±14.28）和DRD2-241 A>G （AA：45.47±17.52;GA：61.82±10.55;GG：75.43±17.71）不同基因型之间均有统计学显著差异（P均<0.01）,而DRD2 Taq1A位点的基因型间PANSS减分率差异无统计学意义。PANSS减分率=58.041-10.703×CYP1A2*1F+4.272×CYP2D6*10-11.921×DRD2-141C Ins/Del+13.443×DRD2-241 A>G （决定系数R²=0.517,P<0.05）。结论 CYP1A2*1F、CYP2D6*10、DRD2-141 C Ins/Del、DRD2-241A>G位点基因多态性影响奥氮平治疗精神分裂症疗效,但只解释了减分率的51.7%,有待纳入更多的影响因素进行分析。     

传统与改良地西泮负荷疗法对酒精戒断性震颤谵妄的疗效比较

目的：探讨改良地西泮负荷疗法对酒精戒断性震颤谵妄的临床疗效。方法：将60例酒精戒断性震颤谵妄患者随机分成地西泮改良负荷疗法组（研究组）和传统地西泮负荷疗法治疗组（对照组），每组各30例。采用酒精戒断综合征评定量表、抑郁自评量表（SDS）、焦虑自评量表（SAS）、临床疗效总评量表（CGI）评定其疗效。结果：研究组戒断综合征评定量表和临床疗效总评量表（CGI）在治疗后第3天、第5天、第7天时的评分显著低于对照组，而且抑郁自评量表（SDS）、焦虑自评量表（SAS）在第5天、第7天的评分也显著低于对照组。结论：地西泮改良负荷疗法治疗酒精戒断性震颤谵妄安全有效。     

Test of association between GABRA2 (SNP rs279871) and adolescent conduct/alcohol use disorders utilizing a sample of clinic referred youth with serious substance and conduct problems,controls and available first degree relatives

Recent findings have linked the GABRA2 gene with antisocial personality disorder and alcohol dependence (AD) in adults and conduct disorder (CD), but not AD symptoms, in children and adolescents. We sought to replicate previous findings and test for an association between a single nucleotide polymorphism (SNP) in the GABRA2 gene (rs279871) and CD among adolescents.MethodsAdolescent patients (n = 371), 13–18 years old, were recruited from a university substance abuse treatment program. Patient siblings (n = 245), parents of patients (n = 355), adolescent controls (n = 185), siblings of controls (n = 163) and parents of controls (n = 263) were included in these analyses (total sample n = 1582). Case-control (using only Caucasian and Hispanic probands) and family-based association tests were completed to test for association between rs279871 and several a priori CD and AD phenotypes.ResultsFor case-control association tests, rs279871 was significantly associated with CD (p = 0.02) but not AD phenotypes; the result did not survive strict correction for multiple testing. All family-based association tests were non-significant (CD p = 0.48; CD symptom count age corrected within sex p = 0.91; AD p = 0.84; alcohol use disorder p = 0.52).ConclusionsConsistent with previous findings, the results do not support the association between GABRA2 SNP rs279871 and AD in adolescents. Our results also do not support an association between rs279871 and CD; the study limitations are reviewed.     

Association of DRD2 polymorphisms and chlorpromazine-induced extrapyramidal syndrome in Chinese schizophrenic patients

AIM: Extrapyramidal syndrome (EPS) is most commonly affected by typical antipsychotic drugs that have a high affinity with the D2 receptor. Recently, many research groups have reported on the positive relationship between the genetic variations in the DRD2 gene and the therapeutic response in schizophrenia patients as a result of the role of variations in the receptor in modulating receptor expression. In this study, we evaluate the role DRD2 plays in chlorpromazine-induced EPS in schizophrenic patients. METHODS: We identified seven SNP(single nucleotide polymorphism) (-141Cins>del, TaqIB, TaqID, Ser311Cys, rs6275, rs6277 and TaqIA) in the DRD2 gene in 146 schizophrenic inpatients (59 with EPS and 87 without EPS according to the Simpson-Angus Scale) treated with chlorpromazine after 8 weeks. The alleles of all loci were determined by PCR (polymerase chain reaction). RESULTS: Polymorphisms TaqID, Ser311Cys and rs6277 were not polymorphic in the population recruited in the present study. No statistical significance was found in the allele distribution of -141Cins>del, TaqIB, rs6275 and TaqIA or in the estimated haplotypes (constituted by TaqIB, rs6275 and TaqIA) in linkage disequilibrium between the two groups. CONCLUSION: Our results did not lend strong support to the view that the genetic variation of the DRD2 gene plays a major role in the individually variable adverse effect induced by chlorpromazine, at least in Chinese patients with schizophrenia. Our results confirmed a previous study on the relationship between DRD2 and EPS in Caucasians.     

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with second-generation antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n=63 and n=54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype–phenotype relationships.     

Pharmacogenetics of Risperidone‐Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder

The purpose of this study was to explore the association of genetic polymorphism of genes related to pharmacokinetics or pharmacodynamics with insulin resistance in children and adolescents with autism spectrum disorder (ASD) and treated with risperidone. All 89 subjects underwent measurement of fasting blood glucose and insulin levels, body‐weight and height. Genotyping was performed by TaqMan real‐time polymerase chain reaction (PCR) (pharmacokinetics genes: cytochrome P450 2D6 (CYP2D6) *4 (rs3892097), *5 (gene deletion), *10 (rs1065852) and *41 (rs28371725), ATP‐binding cassette transporter B1 (ABCB1) 2677 G>T/A (rs2032582) and 3435C>T (rs1045642) and pharmacodynamics genes: dopamine receptor D2 (DRD2) Tag‐SNP (C>T) (rs4436578), DRD2 Tag1A (C>T) (rs1800497), leptin gene (LEP) ‐2548G>A (rs7799039), ghrelin gene (GHRL) ‐604G>A (rs27647) and brain‐derived neurotrophic factor (BDNF) 196G>A (rs6265)). Drug levels were analysed by liquid chromatography–tandem mass spectrometry (LC‐MS/MS). The results revealed that 5 (5.62%) patients presented with hyperglycaemia. Insulin resistance was detected in 15 (16.85%) patients. Insulin resistance was associated with LEP 2548 G>A and BDNF 196 G>A polymorphism (p = 0.051 and p = 0.03). There was no association of pharmacokinetic gene polymorphisms (CYP2D6 and ABCB1) and risperidone levels with insulin resistance. Multiple regression analysis indicated that BDNF 196 G>A polymorphism was significantly associated with insulin resistance (p = 0.025). This finding suggested that BDNF 196 G>A polymorphism may be a genetic marker for predicting insulin resistance before initiating treatment in patients treated with risperidone. Because of the small sample size, further studies are needed to confirm these results.     

Genetic study of BDNF,DRD3, and their interaction in tardive dyskinesia

Tardive dyskinesia (TD) is a neuroleptic-induced movement disorder. Its pathophysiology is unclear. The most consistent genetic findings have shown an association with the Ser9Gly polymorphism of the DRD3 gene. However, only few polymorphisms within DRD3 has been tested, and a comprehensive examination of DRD3 in TD is still lacking. Further, brain-derived neurotrophic factor (BDNF), a neuronal growth and survival peptide, regulates DRD3 expression and may be involved in the neuronal degeneration observed in TD. In the present study, we investigated 15 tag DRD3 polymorphisms and four tag BDNF polymorphisms for association with TD in our sample of Caucasian schizophrenia patients (N = 171). While BDNF markers showed no association, a haplotype containing rs3732782, rs905568, and rs7620754 in the 5′ region of DRD3 was associated with TD diagnosis (p[10,000 permutations] = 0.007). We also found evidence of interaction between BDNF and DRD3 polymorphisms. Further studies are needed to confirm these findings.     

DRD2,DRD4和DAT遗传多态性与云南汉族酒依赖综合征患者的关联研究

背景:酒依赖综合征,也称之为酒依赖,酒精中毒等,是一种渐进性易复发的慢性疾病。酒依赖的发生源于经常性地饮酒过量导致对酒精的渴求,对酒精摄入的失控以及停止饮酒产生的一系列负面情绪等等。世界卫生组织推测酒依赖现已成为发展中国家第三大至死因素。在美国,每年用于酒依赖的支出,包括医疗保健、失业、身体损伤及损伤性质判定,约合1850亿美金。在中国,酒依赖患者的比例呈逐年上升的趋势。目前酒依赖已成为全球关注的一个重要的公共卫生问题。酒依赖综合征是一种复杂疾病,酒依赖的发生与生理、心理、环境及遗传因素等有关。目前酒依赖综合征已被公认为是一种多因素的多基因的复杂疾病,包括基因与基因之间以及基因与环境之间的相互作用。传统的多因素与大样本前瞻性研究提示遗传因素在酒依赖的发病中起重要作用。遗传学研究揭示很多特殊的基因与酒依赖的易感性有关。与酒依赖有关的基因主要包括两类:乙醇代谢相关基因(乙醇脱氢酶、乙醛脱氢酶和细胞色素氧化酶2E1)以及神经递质相关基因(γ-氨基丁酸、儿茶酚氧位甲基转移酶、谷氨酸、多巴胺能系统和阿片系统)。多巴胺与愉悦有关,被称为"抗压分子"或"快乐分子"。当多巴胺被释放至突触,它刺激一系列的受体发挥作用。多巴胺能系统中的多巴胺受体D2、多巴胺受体D4和多巴胺转运体的遗传多态性可能与酒依赖有关。然而,多巴胺能系统中相关基因的遗传多态性与酒依赖的相关性目前尚无定论。目的:本研究通过研究多巴胺D2受体基因中TaqIA、TaqIB、-141CIns/Del,多巴胺转运体基因3′末端非编码区40bp可变数目串联重复序列和多巴胺D4受体基因第3外显子上48bpVNTR多态性,探讨多巴胺能系统遗传多态性与酒依赖综合征的相关性,为探索酒精依赖综合征的发病机理及其基因诊断和治疗提供科学的依据。方法:按照DSM-Ⅳ诊断标准选择酒精依赖综合征病例样本。主要的选择标准包括:(1)过去的六个月内日饮酒量超过6听啤酒;(2)年龄在21-79a之间;(3)追溯三代均为云南汉族;(4)有知情同意能力;(5)除烟草和咖啡因依赖以外,过去的6月内没有使用其他成瘾物质;(5)无其他精神疾病,如精神分裂症、重度抑郁症和躁狂抑郁症等。选择与之匹配的非酒依赖个体作为对照样本。共采集病例组样本80例,对照组样本70例。各样本抽取静脉血3ml,EDTA-Na2抗凝处理,通过饱和酚/氯仿法提取DNA,采用聚合酶链式反应-限制性片断长度多态性(PCR-RFLP)分析技术以及聚合酶链式反应-可变数目串联重复序列多态性(PCR-VNTR)分析技术检测酒依赖组和对照组在3个候选基因中的基因型和等位基因频率。应用SPSS15.0和HWSIM软件进行统计学分析。结果:共检测了云南汉族群体三个候选酒依赖相关基因的5个SNP位点,其中病例80,对照70例。DRD2基因TaqIA多态性在病例组和对照组中共检出2种等位基因:A1和A2。3种基因型:TaqIA1/A1、TaqIA1/A2、TaqIA2/A2。其中,患者组中TaqIA1/A1基因型为7例(8.8%),TaqIA1/A2基因型为45例(56.3%),TaqIA2/A2基因型为28例(35%);对照组中TaqIA1/A1基因型为15例(21.4%),TaqIA1/A2基因型为30例(42.9%),TaqIA2/A2基因型为25例(35.7%)。DRD2基因TaqIB多态性在两组中共检出2种等位基因:B1和B2。3种基因型:TaqIB1/B1(野生型纯合子)、TaqIB1/B2(杂合子)、TaqIB2/B2(突变型纯合子)。其中,患者组中TaqIB1/B1基因型为29例(36.3%),TaqIB1/B2基因型为46例(57.5%),TaqIB2/B2基因型为5例(6.3%);对照组中TaqIB1/B1基因型为21例(30%),TaqIB1/B2基因型为33例(47.1%),TaqIB2/B2基因型为16例(22.9%)。DRD2基因-141CIns/Del多态性在两组中共检出2种等位基因:-141CIns和-141CDel。3种基因型:-141CDel/Del、-141CIns/Del、-141CIns/Ins。其中,患者组中-141CDel/Del基因型为1例(1.3%),-141CIns/Del基因型为12例(15%),-141CIns/Ins基因型为67例(83.8%);对照组中只检出2种基因型,即-141CIns/Del和-141CIns/Ins。其中,-141CIns/Del基因型为11例(15.7%),-141CIns/Ins基因型为59例(84.3%)。DAT基因40bpVNTR多态性在两组中共检出4种等位基因:8、10、11和12。观察到5种基因型:11/8、10/10、11/11、11/10、12/11。其中,患者组中11/8基因型为1例(1.3%),10/10基因型为1例(1.3%),11/11基因型为66例(83.5%),11/10基因型为6例(7.5%),12/11基因型为6例(7.5%);对照组中基因型11/8为1例(1.4%),10/10为2例(2.9%),11/11为55例(78.6%),11/10为10例(14.3%),12/11为2例(2.9%)。DRD4基因48bpVNTR多态性在两组中共检出2种等位基因,分别是2和4。观察到2种基因型:2/2和2/4。其中,患者组中2/2基因型为62例(77.5%),2/4基因型为18例(22.5%);对照组中2/2基因型为62例(88.6%),2/4基因型为8例(11.4%)。上述5个候选基因中,DRD2基因TaqIB多态性的基因型和等位基因频率,统计学分析在酒依赖组和对照组中有差异(P<0.05),具有统计学意义。其余4个位点统计学分析差异均无显著性(P>0.05)。研究结果提示TaqIB多态性与酒依赖相关,进一步对TaqIB进行logistic回归分析时,结果显示携带B2等位基因者能显著降低其嗜酒的发生率(OR:0.225,P<0.05)。同时,在对DRD2基因中的TaqIB、DAT基因40bpVNTR和DRD4基因48bpVNTR进行组合基因型分析时,结果显示:以H1(B1-B1-11-11-2-2)组合基因型为参考时,H14(B2-B2-11-11-2-2)属于酒精依赖综合征的一种保护因素(OR:0.133,P<0.05)。结论:本研究提示,在云南地区汉族人群中,DRD2基因TaqIA、-141C以及DRD4基因48bpVNTR和DAT基因40bpVNTR与酒依赖无关联性,而DRD2基因TaqIB多态性与酒依赖存在相关性,携带B2等位基因者能显著降低其嗜酒的发生率。并且,以H1(B1-B1-11-11-2-2)组合基因型为参考时,H14(B2-B2-11-11-2-2)属于酒依赖综合征的一种保护因素。     

Intramuscular/oral lorazepam in acute alcohol withdrawal and incipient delirium tremens

Summary

An open study was carried out in 21 chronic alcoholics with severe withdrawal symptoms and incipient delirium tremens to evaluate the efficacy of adjuvant treatment with intramuscular lorazepam (5?mg). All symptoms subsided within 2 hours after a single injection and remained under control with oral lorazepam (mean daily dose 7?mg). No adverse reactions attributable to lorazepam were observed.     

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。     

VKORC1-3673G>A、CYP2C9*3、CYP4F2 rs2108622和CYP2C19*2基因多态性对中国汉族房颤患者华法林维持剂量的影响

目的 探讨VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622和CYP2C19^*2位点基因多态性对中国汉族房颤患者华法林维持剂量的影响。方法 收集107例服用华法林达维持剂量的汉族房颤患者的血样和临床相关资料,应用PCR-RFLP法检测VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622和CYP2C19^*2基因型,采用独立样本t检验分析基因型与华法林维持剂量的相关性。多元线性回归建立给药模型,探讨基因多态性对华法林维持剂量的影响。结果 VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622基因多态性和患者年龄、体质量能解释45.2%的华法林维持剂量差异。CYP2C19^*2基因多态性对本研究人群华法林维持剂量无影响。结论 VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622基因多态性显著影响中国汉族房颤患者的华法林维持剂量。     

Effect of UGT1A1, UGT1A3, DIO1 and DIO2 polymorphisms on L-thyroxine doses required for TSH suppression in patients with differentiated thyroid cancer

AimTo evaluate the impact of genetic polymorphisms in uridine 5′-glucuronosylytansferases UGT1A1 and UGT1A3 and iodothyronine-deiodinases types 1 and 2 on levothyroxine (T₄; 3,5,3′,5′-triiodo-L-thyronine) dose requirement for suppression of thyrotropin (TSH) secretion in patients with differentiated thyroid cancer (DTC).MethodsPatients (n = 268) submitted to total thyroidectomy and ablation by ¹³¹I, under T₄ therapy for at least 6 months were recruited in three public institutions in Brazil. Multivariate regression modelling was applied to assess the association of T₄ dosing with polymorphisms in UGT1A1 (rs8175347), UGT1A3 (rs3806596 and rs1983023), DIO1 (rs11206244 and rs2235544) and DIO2 (rs225014 and rs12885300), demographic and clinical variables.ResultsA regression model including UGT1A haplotypes, age, gender, body weight and serum TSH concentration accounted for 39% of the inter-individual variation in the T₄ dosage. The association of T₄ dose with UGT1A haplotype is attributed to reduced UGT1A1 expression and T₄ glucuronidation in liver of carriers of low expression UGT1A1 rs8175347 alleles. The DIO1 and DIO2 genotypes had no influence of T₄ dosage.ConclusionUGT1A haplotypes associate with T₄ dosage in DTC patients, but the effect accounts for only 2% of the total variability and recommendation of pre-emptive UGT1A genotyping is not warranted.     

DRD2基因多态性与冠状动脉旁路移植术后谵妄的关联研究

目的 研究DRD2基因多态性与冠状动脉旁路移植术后谵妄的相关性以及危险因素.方法 以冠状动脉旁路移植手术住院患者为研究对象,连续纳入手术患者150例,以《谵妄分级量表-98修订版》作为谵妄诊断工具,分析术后谵妄的发生率和危险因素;采用基因测序法确定DRD2的多态性,分析rs6275、ts6277多态性与谵妄的相关性.结果 术后谵妄发生率8.0%(12/150例);组间单因素分析显示脑梗死 (OR=0.784,95%CI 0.631～0.975,P=0.024);手术持续时间(OR=2.251,95%CI 0.941～5.380,P=0.048);体外循环时间(OR=1.057,95%CI 0.703～1.590,P=0.029);ICU病房时间(OR=1.890,95%CI 1.201～2.973,P=0.005)差异有统计学意义(P<0.05);2组间rs6275基因型差异无统计学意义(OR=1.265,95%CI 0.697～2.303,P=0.651);rs6277基因型2组间分布差异有统计学意义(OR=2.276,95%CI 1.142～4.523,P=0.049);Logsistic多因素回归分析显示脑梗死(OR=1.861,95%CI 1.082～3.163,P=0.024)、ICU持续时间(OR=6.757,95%CI 2.376～19.267,P=0.001)、rs6277的CC基因型(OR=4.019,95%CI 1.395～12.341,P=0.012)是术后谵妄的危险因素.结论 对术前合并脑梗死的高危患者,进行DRD2基因筛查,有助于评估谵妄发生的可能性.