广泛性焦虑障碍与5-羟色胺转运体基因多态性的相关研究

目的　探讨广泛性焦虑障碍与 5 羟色胺转运体 (5 HTT)基因启动子区和内含子 2区两种多态性的相关性。方法　运用聚合酶链反应技术检测 4 7例广泛性焦虑障碍患者 (患者组 )和 90名健康对照者 (对照组 )两种基因多态性的分布频率。结果　患者组启动子区多态性 (5 HTTLPR)的short/short(SS)基因型和short(S)等位基因频率分别为 72 %和 83% ,对照组SS基因型和S等位基因频率分别为 4 9%和 71% ,两组间的差异有显著性 (P <0 0 5 )。内含子 2区数目可变的顺向重复多态性各基因型 (12 / 12 ,12 / 10 ,10 / 10 )频率在患者组中分别为 72 % ,2 6 % ,2 % ,在对照组中分别为 78% ,2 1% ,1% ,两组间的差异无显著性 (P >0 0 5 ) ;等位基因频率比较的差异亦无显著性 (P >0 0 5 )。结论　 5 HTTLPR的SS基因型可能是广泛性焦虑障碍的易感基因之一。     

A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety

Studies of the association between polymorphisms of the serotonin transporter gene (5-HTT) and trait anxiety have produced inconsistent results, raising questions about the strength of the relationship and the methodological conditions under which the relationship holds. We conducted a meta-analysis of existing studies to provide formal statistical measures of the strength of the linked polymorphic region of the serotonin transporter gene (5-HTTLPR)-anxiety relationship. For the entire collection of 26 studies, results provided no support for a relationship between anxiety and the presence of the short form of the 5-HTTLPR polymorphism. There was strong evidence of the presence of moderating variables, however, and subsequent analysis revealed that choice of the measure of trait anxiety was significant. Studies using the Neuroticism scale of Costa and McCrae were found to produce a small positive effect (d=0.23). Other potential moderators (country of study origin, type of subject) did not have a meaningful impact on d statistics. These findings indicate that 5-HTTLPR may in fact have a small but reliable influence on personality, particularly in the manifestation of trait anxiety when measured with a neuroticism scale based on the five-factor model of personality. Our results suggest that the success of future personality genetics research will be maximized by the use of personality measures from both the psychobiological and five-factor models.     

Possible association between serotonin transporter gene polymorphism and violent suicidal behavior in mood disorders.

BACKGROUND: Genes involved in the serotonin system are major candidates in association studies of suicidal behavior. In this case-control study we investigated whether the serotonin transporter (5-HTT) gene encoding the protein responsible for the reuptake of serotonin from the synapse after its release from serotonergic neurons is a susceptibility factor for suicidal behavior. METHODS: A functional polymorphism of the 5-HTT gene (a 44-base pair insertion/deletion in the 5-HTT-linked polymorphic region [5-HTTLPR]) was studied in a population of 237 consecutive patients with affective disorder (unipolar or bipolar) and 187 control subjects. Ninety-nine patients had attempted suicide at least once, of whom 26 made a violent attempt. RESULTS: No association was found between the "s" allele of the 5-HTTLPR and suicide attempt; however, there was a significant difference in allele distributions between patients who had made violent suicide attempts and control subjects. CONCLUSIONS: A genetic variant of the 5-HTT gene may predispose individuals to violent suicidal behavior. The precise phenotype associated with the 5-HTT gene is unclear, and therefore further studies are required to replicate these findings.     

Gender difference in association between polymorphism of serotonin transporter gene regulatory region and anxiety

OBJECTIVE: The objective of this study was to verify the hypothesis that variation of the serotonin transporter gene promoter region (5-HTTLPR) is associated with sensitivity to stress. METHODS: Genotyping of 5-HTTLPR and evaluation of emotional states were performed on 194 participants. Participants' emotional states were evaluated using the Perceived-Stress Scale (PSS), the State-Trait Anxiety Inventory (STAI), and the Self-rating Depression Scale (SDS). RESULTS: There was significant GenderxGenotype interaction in STAI (state, P<.05; trait, P<.05). Females with the l/s genotype showed higher anxiety than those with the s/s genotype in both state and trait anxiety. Oppositely, males with the s/s genotype showed higher anxiety than those with the l/s genotype. CONCLUSION: On all emotional scales, females with the l/s genotype showed high scores, contrary to males with the same genotype. Therefore, our results suggest that 5-HTTLPR l allele may be one pathway that activates negative emotion in females but acts contrary in males.     

Blushing propensity in social anxiety disorder: influence of serotonin transporter gene variation

Blushing is considered to be one of the prime pathophysiological markers of social anxiety disorder, potentially mediated by serotonergic function. Therefore, in the present study 62 patients with social anxiety disorder and 62 age- and sex-matched healthy controls were investigated for the influence of serotonin transporter (5-HTT) gene variation (5-HTTLPR, rs25531) on blushing propensity as measured by the blushing propensity scale (BPS). The less active 5-HTTLPR genotypes were nominally significantly associated with increased blushing propensity in patients with social anxiety disorder as compared to controls with an equidirectional trend for the less active 5-HTTLPR/rs25531 haplotypes. Even when statistically controlled for influence of depression, this association remained significant. In summary, the present pilot study suggests a potential role of functional serotonin transporter gene variation in blushing propensity warranting replication and encouraging genetic analyses of further intermediate phenotypes of social anxiety disorder. Katharina Domschke and Stephan Stevens contributed equally to this work and should therefore both be considered first authors.     

Association for serotonin transporter gene variable number tandem repeat polymorphism and schizophrenic disorders

In contrast with two previous western reports, a recent study on a Chinese population found an association for allele 12 of the variable number tandem repeat (VNTR) in the second intron of the serotonin transporter (5-HTT) gene and schizophrenic disorders. We have replicated this finding for a Chinese population in Taiwan (114 schizophrenic patients and 127 controls), demonstrating a modest but significant statistical association for the 5-HTT-VNTR allele 12 and schizophrenic patients (one-sided p = 0.043). This positive finding further supports the proposition that the 5-HTT-VNTR allele 12 is a risk factor for schizophrenic disorders in Chinese populations, although the effect is weak.     

Organization of the human serotonin transporter gene

Summary The gene encoding the human serotonin transporter (5-HTT) has been isolated and characterized. The human 5-HTT gene is composed of 14 exons spanning 31 kb. The sequence of all exons including adjacent intronic sequences and a tandem repeat DNA polymorphism (VNTR) has been determined and deposited in the EMBL/GenBank data base with the accession numbers X76753 to X76762. The characterization of 5-HTT gene will aid to advance molecular pharmacologic studies of 5-HT uptake regulation and facilitate investigations of its role in psychiatric disorders.     

5-羟色胺转运体基因启动子区与心境障碍的关联分析

目的 探讨5-羟色胺转运体基因启动子区5-HTTLPR与心境障碍之间的分子遗传学联系。方法 在中国汉族人群中,以心境障碍核心家系作为研究对象,根据哈佛大学提供的遗传学研究用诊断性检查表(DIGS)自编家系调查表,采用DSM-Ⅳ诊断标准并结合一些心理测评工具,以达到表型一致。在72个情感性精神障碍核心家系,222个家系成员(其中双相障碍56例,重性抑郁症34例)中,应用聚合酶链反应(PCR)和限制性片段长度多态性方法,对5-HTT基因启动子区5-HTTLPR与心境障碍之间的分子遗传学联系进行了以家系为基础的连锁不平衡分析结果基因型和等位基因频率在心境障碍患病组和父母对照组之间无显著差异。GHRR和HHRR分析以及多等位基因ETDT统计分析也没有发现存在连锁不平衡。5-HTTLPR位点除了“L”和“S”片段外,还发现2例出现“L^*”(528^*bp)片段,频率约占1％。结论 5-HTYLPR在心境障碍的发病中可能不起重要作用。     

Significance of serotonin transporter gene polymorphism in migraine.

OBJECTIVE: To elucidate significance of the serotonin transporter gene (STG) polymorphism in migraine, and to address the polymorphic patterns of STG, both in the migraineurs and healthy people in this country. STUDY DESIGN: A PCR study of STG in 52 migraineurs and 80 healthy controls. METHODS: Using the PCR technique, STG polymorphism was studied in the DNA obtained from leukocytes of the patients and healthy controls. Polymorphism of the two regions (VNTR and 5-HTTLPR) of STG was assessed. RESULTS: VNTR STin 2.10 and STin 2.12 alleles were detected in migraineurs and healthy controls. Both homozygous and heterozygous STin 2.10 allele predominated in the migraine group (p=0.01), while STin 2.12 allele was more frequent in the healthy controls (p=0.02). There was no relationship between the migraine type, family history of migraine and STG polymorphism. CONCLUSION: STin 2.10 and STin 2.12 alleles of VNTR are frequent in this country. While the presence of STin 2.10 allele increases the risk of migraine, 5-HTTLPR polymorphism is not associated with this risk.     

Association between serotonin transporter gene polymorphism and anxiety-related traits.

BACKGROUND: Polymorphism in the serotonin transporter promoter gene has been recently reported to be associated with the personality trait known as anxiety-related traits. We have attempted to replicate these findings in 101 healthy Japanese subjects. METHODS: The personality traits of the subjects were assessed with the tridimensional personality questionnaire. RESULTS: An association was observed in the present study between individuals grouped according to the transporter gene and harm avoidance scores. CONCLUSIONS: These data supported that there was an association between the serotonin transporter gene and anxiety.     

A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders

The different 5-HT (serotonin) receptors including the serotonin transporter (5-HTT) are candidate genes for affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). They have been investigated in a number of allelic association studies where the individual results have been inconsistent, and therefore, definite conclusions are difficult to make. Systematic reviews using meta-analytical techniques are a reliable method for objectively and reproducibly assessing individual studies and generating combined result. This study aimed at reviewing published studies investigating the association between affective disorders (MDD and BD) and variation at genes coding for serotonin receptors and the serotonin transporter. We performed National Library of Medicine database searches to identify potential studies. More than 430 articles were reviewed and 86 studies met the inclusion criteria for participation in our review. Of these, 41 studies investigated 45 different 5-HT receptor variants and 45 studies investigated at least one of two commonly studied 5-HTT polymorphisms in MDD. Many studies investigated the association between MDD and BD with the 5-HT2A 102 T/C, the 5-HTT promoter 44 bp insertion/deletion and the intron 2 VNTR polymorphisms, and thus, these could be pooled using meta-analytic techniques. The overall odds ratio (OR) for the combined individual results was significant for BD and the two 5-HTT polymorphisms: Mantel-Haenszel weighted OR=1.14, CI: 1.03-1.26, P=0.015 for the promoter locus (N=3467) and Mantel-Haenszel Weighted odds ratio OR=1.18, CI: 1.05-1.32, P=0.004 for the VNTR locus (N=3620). However, sensitivity analysis indicated that, in each case, the overall positive association could be mostly attributed to the large effect of one individual study. Therefore, these results suggest that, although promising, further studies are required to assess appropriately the evidence suggesting an association between BD and 5-HTT.     

The serotonin transporter gene and Parkinson's disease

Dysfunction in the serotonin (5-hydroxytryptamine) system and reduced serotonin concentrations have been reported in patients with Parkinson's disease (PD). Serotonin concentrations in neural tissue are controlled by a presynaptic serotonin transporter protein that is encoded by a single gene. Therefore, we investigated whether a polymorphic region in the serotonin transporter gene is associated with PD. Three variable-number tandem repeat (VNTR) elements of the serotonin transporter gene were detected by polymerase chain reaction, those with 9, 10, 11 and 12 copies of the repeat element. The 10-copy VNTR element was significantly less common in patients with PD than controls in the univariate analysis (p < 0.05). Logistic regression analysis revealed no significant differences between patients (n = 198) and controls (n = 200) in the distribution frequencies of 9- and 12-copy alleles and combined genotypes (odds ratio = 1.20; p = 1.71). A positive family history of PD was a strong predictor of disease risk (odds ratio = 2.98; 95% confidence interval 1.51-5.87; p = 0.001). Although slight differences were observed between patient and control groups, these data suggest that defects in serotonin concentrations in patients with PD are unlikely to be due to polymorphisms in the serotonin transporter gene in this large Australian cohort; however, the inverse association observed with the 10-copy allele warrants further investigation.     

5-羟色胺转运体基因多态性与精神分裂症的相关性研究

目的：探讨中国汉族人群中5一羟色胺转运体（5-HTT）基因与精神分裂症之间的相关性。方法：189例符合中国精神障碍分类与诊断标准第3版及美国精神障碍诊断与统计手册第4版精神分裂症诊断标准的患者（患者组）使用聚合酶链式反应扩增5-HTT基因的启动子区（5-HTrLPR）位点和内含子区（5-HTTVNTR）位点,以琼脂糖凝胶电泳分离法进行基因分型,并和300名正常人（正常对照组）进行对照。结果：患者组与正常对照组之间5-HTTLPR位点L／L、L／S和S／S基因型频率以及等位基因L、s频率分布上差异具有统计学意义（x2=47．882,x2=44．188;P〈0．01或P〈0．001）;5-HTTVNTR位点12／12、12／10、10／10基因型频率和等位基因10、12频率分布上差异无统计学意义（X2=0．335,X。=0．051;P均〉0．05）。结论：S／S基因型及S等位基因可能是精神分裂症患者的易感等位基因;5-HT．TVNTR位点在中国汉族人群精神分裂症发病机制中可能不起主要作用。     

Functional polymorphism within the promotor of the serotonin transporter gene is associated with severe hyperkinetic disorders

In children and adolescents, hyperkinetic disorder (HD) with conduct disorder (CD) and without CD and attention-deficit/hyperactivity disorder (ADHD) is known to be comorbid with psychiatric disorders (anxiety, depression, aggression), some of which are related to disturbed serotonergic neurotransmission. The efficiency of serotonergic signalling relates to the concentration of the neurotransmitter in the synaptic cleft and is controlled by the serotonin transporter (5-HTT), which selectively removes serotonin out of the synaptic cleft.(1)The activity of serotonin transport itself has been shown to be also controlled by a 5-HTT-linked polymorphism in its promotor region with a L/L genotype yielding higher levels of 5-HTT function than do L/S or S/S genotypes.(2) Considering an association between 5-HTT polymorphism, serotonergic neurotransmission and HD +/- CD, we genotyped for 5-HTT polymorphism and compared patients with controls. In contrast to the distribution of L/L: L/S: S/S in controls (0.245: 0.509: 0.245), we found an enhanced expression of the L/L genotype in HD patients with CD (0.393: 0.304: 0.304; chi(2) = 7.603; P = 0.0211) and a significant overexpression of L/L in HD without CD (0.542: 0.333: 0.125; chi(2) = 9.127; P = 0.0092). To our knowledge, this is the first finding providing evidence for an association between the 5-HTT polymorphism and hyperkinetic disorder, implying that serotonergic neurotransmission might be affected in this desease. As a consequence, for a successful treatment of these patients one should now also consider drugs which specifically modulate serotonergic signalling such as selective serotonin reuptake inhibitors.     

No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism.

BACKGROUND: A polymorphism in the serotonin transporter promoter gene region (5-HTTLPR) has been shown to influence the quantity of serotonin transporter expressed in human cell lines: the 5-HTTLPR short allele (s) has been associated with reduced 5-HTT expression when compared to cells carrying the 5-HTTLPR long allele (l). We performed a single photon emission computed tomography (SPECT) study using the ligand [(123)I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT) to measure 5-HTT availability in 16 healthy subjects genotyped for 5-HTTLPR. METHODS: SPECT scans were performed 24 hours after tracer injection, regions of interest anatomically corresponding to the thalamus-hypothalamus and mesencephalon-pons areas were compared to the binding in the cerebellum, representing the nondisplaceable [(123)I]-beta-CIT-binding (results expressed as target activity minus cerebellum activity/cerebellum activity). DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods. RESULTS: Specific binding ratios in the thalamus-hypothalamus were 2.65 +/- 0.4 in subjects with the l/l genotype (n = 3), 2.76 +/- 0.5 in subjects with the l/s genotype (n = 9), and 2.77 +/- 0.4 in subjects with the s/s genotype (n = 4). Binding ratios in the mesencephalon-pons were 1.43 +/- 0.3 (l/l; n = 3), 1.37 +/- 0.3 (l/s; n = 9), and 1.28 +/- 0.3 (s/s; n = 4). None of these differences was statistically significant. CONCLUSIONS: Our data provide no evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects.     

The serotonin transporter gene and effectiveness of SSRIs

The definition of a genetic liability profile for specific antidepressant treatment will soon be available, offering considerable help in early detection of effective therapy in mood disorders. The search for genetic factors predisposing to drug response or side effects in mood disorders started only in the last few years. The efficacy of antidepressant action was associated with several polymorphisms, located on coding genes of proteins thought to be involved in the different mechanisms of action of antidepressant treatments. Among these, gene variants in sequences of serotonin pathway proteins were candidates, both for the well-known evidence of its involvement in the development of depressive symptoms and for the worldwide use of selective serotonin reuptake inhibitors as first-choice treatment of depression. A polymorphism in the promoter region of the serotonin transporter (SERTPR) was independently associated with efficacy for a range of treatments. This article reviews the pharmacogenetic studies published to date, focusing the attention on the SERTPR.     

Genetic bases of comorbidity between mood disorders and migraine: possible role of serotonin transporter gene

Migraine is a common neurological disease in the population and the most associated headache with mood disorder. Although the relationship between migraine and depression is well known, the reverse correlation between depression and migraine was observed but not well understood. The tight relationship between the two disturbances is also suggested by the efficacy of antidepressants for migraine treatment. Starting from these observations, we can presume that both migraine and depression have overlapping biological bases. The main target of antidepressant treatments belonging to the serotonin selective reuptake inhibitors (SSRI) type is the serotonin transporter (SERT); a well-studied polymorphic variant, in the promoter region of the gene (SERTPR), has been demonstrated to influence the availability of serotonin in the synaptic cleft. So, our group studied the possible role of the SERT as a risk factor, both for migraine and mood disorders, in a sample of 96 patients affected by both pathologies.