The 5‐HT2A receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed patients

Several lines of evidence suggest that genetic factors constitute an important determinant of suicidal behavior. A significant association between the 5‐HT_2A‐C allele and suicidality has recently been reported. The aim of this study was to investigate whether the proposed association between 5‐HT_2A‐102T/C polymorphism and suicidality could be replicated in a larger and independent sample of Spanish patients with major depression. The 102T/C polymorphism of the 5‐HT_2A receptor gene was analyzed in 159 patients with major depression (DSM‐IV criteria) and 164 unrelated and healthy controls using a case control design. All individuals were subjects of Spanish origin. Significant differences in allele (chi‐square = 4.13, df = 1, P = 0.04) and genotype (chi‐square = 6.19, df = 2, P = 0.04) distributions were found between non–suicide attempters and suicide attempters. Moreover, those patients carrying 5‐HT_2A‐C allele had more than five times the risk for attempting suicide than noncarriers (OR = 5.50, 95% CI = 1.18–35.20, P = 0.01). Our results replicate the proposed association between 5HT_2A‐C allele and suicidality in major depression. Moreover, no overall associations are detected when patients with major depression and controls are compared for 102T/C frequencies, suggesting that the increased risk for suicidality conferred by 5‐HT_2A‐C allele is primarily associated with suicidal behavior and not with the diagnosis of major depression itself. © 2001 Wiley‐Liss, Inc.     

Association between 5-hydroxytryptamine 2A receptor gene polymorphism and postoperative analgesic requirements after major abdominal surgery

Although the serotonin (5-hydroxytryptamine (5-HT)) 2A receptor has been reported to be associated with pain, no relationship has been found between single nucleotide polymorphisms in the 5-HT2A receptor gene and analgesic requirements. To clarify the mechanism of individual differences in analgesic requirements, we investigated the relationship between the 5-HT2A 102T/C gene polymorphism and analgesic requirements in 135 patients who underwent major open abdominal surgery and were managed with continuous epidural analgesia with opioids after surgery. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. We found that the 102T/C polymorphism had significant main effects with regard to analgesic requirements. In addition, significant interaction effects were found between the 102T/C polymorphism and sex in terms of analgesic requirements. Among female subjects, patients with the T/T genotype of the 102T/C polymorphism had more analgesic requirements than those with the other genotypes. This finding suggests that the linkage disequilibrium block, which includes the 102T/C polymorphism of the 5-HT2A receptor gene, is involved in individual differences in analgesic requirements in women.     

Selective 5HT2A and 5HT6 receptor antagonists promote sleep in rats

STUDY OBJECTIVES: Serotonin (5-HT) has long been implicated in the control of sleep and wakefulness. This study evaluated the hypnotic efficacy of the 5-HT6 antagonist RO4368554 (RO) and the 5-HT2A receptor antagonist MDL100907 (MDL) relative to zolpidem. DESIGN: A randomized, repeated-measures design was utilized in which Wistar rats received intraperitoneal injections of RO (1.0, 3.0, and 10 mg/kg), MDL (0.1, 1.0 and 3.0 mg/kg), zolpidem (10 mg/kg), or vehicle in the middle of the dark (active) period. Electroencephalogram, electromyogram, body temperature (Tb) and locomotor activity were analyzed for 6 hours after injection. MEASUREMENTS AND RESULTS: RO, MDL, and zolpidem all produced significant increases in sleep and decreases in waking, compared with vehicle control. All 3 doses of MDL produced more consolidated sleep, increased non-rapid eye movement sleep (NREM) sleep, and increased electroencephalographic delta power during NREM sleep. The highest dose of RO (10.0 mg/kg) produced significant increases in sleep and decreases in waking during hour 2 following dosing. These increases in sleep duration were associated with greater delta power during NREM sleep. ZO Zolpidem induced sleep with the shortest latency and significantly increased NREM sleep and delta power but also suppressed rapid eye movement sleep sleep; in contrast, neither RO nor MDL affected rapid eye movement sleep. Whereas RO did not affect Tb, both zolpidem and MDL reduced Tb relative to vehicle-injected controls. CONCLUSIONS: These results support a role for 5-HT2A receptor modulation in NREM sleep and suggest a previously unrecognized role for 5-HT6 receptors in sleep-wake regulation.     

自杀未遂与5-羟色胺2A受体基因的关联分析

目的 探讨5-羟色胺（5-HT）2A受体基因A-1438G和T102C两种多态性与自杀未遂之间的关系。方法 以149例自杀未遂者为研究对象。190名正常人为对照,采用聚合酶链反应-限制性片段长度多态性（polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)方法,分析5-HT2A受体基因A-1438G和T102C多态性。结果 PCR-RFLP分析发现,男性自杀未遂与5-HT2A受体基因A-1438G多态性的基因型GG关联。结论 5-HT2A受体基因A-1438G多态性可能与男性的自杀易感性相关。     

Association of thromboxane A2 receptor gene polymorphism with the phenotype of acetyl salicylic acid-intolerant asthma

BACKGROUND AND OBJECTIVE: The thromboxane A2 receptor (TBXA2R) is a receptor for a potent bronchoconstrictor, TBXA2 which is known to be related to bronchial asthma and myocardial infarction. TBXA2R antagonist and TBX synthase inhibitors have been found to be effective in the management of asthmatic patients. This study was aimed to evaluate whether genetic variants of TBXA2R may be related with development of acetyl salicylic acid (ASA)-intolerant asthma (AIA). METHODS: TBXA2R gene polymorphisms (TBXA2R+795T>C, TBXA2R+924T>C) were determined using a single-base extension method in 93 AIA patients compared with 172 patients with ASA-tolerant asthma (ATA) and 118 normal controls (NCs) recruited from the Korean population. HLA DPB1*0301 genotype was performed using a direct sequencing method. RESULTS: The rare C allele frequency of TBXA2R+795T>C was significantly higher in AIA than in ATA (P=0.03) and the TBXA2R+795T>C polymorphism was also associated with extent of percent fall in forced expiratory volume in 1 s (FEV1) after the inhalation of lysine-acetyl salicylic acid in AIA patients (P=0.009); AIA patients homozygous for the +795 C allele had a greater percent fall of FEV1 compared with individuals with TBXA2R+795 CT or TT genotypes. The frequency of patients carrying both the TBXA2R+795T>C rare allele and HLA DPB1(*)0301 was significantly higher in AIA patients (29.4%) than in ATA patients (7.3%) (P=0.008, odds ratio=5.3). CONCLUSION: These results suggest that the polymorphism of TBXA2R+795T>C may increase bronchoconstrictive response to ASA, which could contribute to the development of the AIA phenotype.     

Association of a serotonin receptor 2A gene polymorphism with cognitive functions in patients with schizophrenia.

The aim of this study was to investigate the association between the T102C polymorphism on the 5HT2A gene and cognitive function as well as clinical manifestations in patients with schizophrenia. Eighty-two outpatients with schizophrenia participated in this study. The Brief Psychiatric Rating Scale (BPRS) was used to assess the severity of each patient's symptoms. In order to evaluate their short-term attention capacity, a Digit Span Test was used. The Continuous Performance Test (CPT) was used to test the sustained attention span of each of the subjects. Cognitive flexibility was measured with the Wisconsin Card Sorting Test (WCST). The polymorphism of the 5-HT2A gene at codon 102 (T/C) was genotyped by sequence specific polymerase chain reaction. The T allele at codon 102 correlated with a lower hit rate and more commission errors in the CPT and patients with the heterogeneous genotype (TC) had more commission errors than those who were of homogeneous type (CC or TT). Patients with the TC genotype also had significantly fewer correct responses in the WCST compared to those who were type CC or TT. No relationship was found to exist between the C allele and cognitive variables. There was also no relationship established between the codon 102 polymorphism and clinical parameters. These findings suggest that the TC genotype might be related to certain cognitive impairments in patients with schizophrenia.     

A family-based study of the Cys23Ser 5HT2C serotonin receptor polymorphism in schizophrenia

The 5HT2C receptor has a high affinity for clozapine, a nontypical neuroleptic, and has therefore been postulated to play a role in mediating negative symptoms and neuroleptic response in schizophrenia. In the current study, the Cys23Ser 5HT2C serotonin receptor polymorphism was examined for linkage to schizophrenia by genotyping 207 nuclear families consisting of both parents and schizophrenic child and using the transmission disequilibrium test to examine possible preferential transmission of these alleles from 68 heterozygous mothers to their ill child. No evidence was obtained for preferential transmission of the Cys23Ser 5HT2C alleles in schizophrenia in either of the two main ethnic groups examined (German and Palestinian Arab) or in the combined cohort (TDT chi-square = 0.00, NS).     

Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder

There is evidence indicating that density of 5-HT2A receptors is altered in brain regions of depressed suicide victims and in platelets of suicidal subjects with major depression or schizophrenia. Recent studies have also shown an association between the allele C of 102T/C polymorphism in the 5-HT2A receptor gene and schizophrenia. The present investigation tested the hypothesis that the observed changes in 5-HT2A receptor density in platelets of patients with major depression are a trait rather than state phenomenon and are associated with the 102 C allele in 5-HT2A receptor gene in a sample of 120 patients with major depression and a group of 131 control subjects comparable with respect to age, sex, and ethnic background. The allele and genotype frequencies of 102T/C polymorphism in 5-HT2A receptor gene were compared between patients and control subjects and between suicidal and non-suicidal patient groups. The major finding of this study was a significant association between the 102 C allele in 5-HT2A receptor gene and major depression, chi(2) = 4.5, df = 1, P = 0.03, particularly in patients with suicidal ideation, chi(2) = 8.5, df = 1, P < 0.005. Furthermore, we found that patients with a 102 C/C genotype had a significantly higher mean HAMD item 3 score (indication of suicidal ideation) than T/C or T/T genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:56-60, 2000.     

Polymorphism of 5HT2A serotonin receptor gene is implicated in smoking addiction.

Smoking behavior is influenced by genetic factors. Polymorphisms affecting the dopaminergic system have been linked to smoking habits. The aim of this study was to investigate if the T102C polymorphism of the 5-HT(2A) receptor gene is related to tobacco use, since this receptor modulates the mesolimbic dopamine system and the C allele is associated with reduced receptor gene expression. A sample of 625 subjects were genotyped and classified according to their smoking behavior (never, former, or current smokers). We found differences in the distribution of the genotypes when the current smokers were compared with the never + former smokers, suggesting that T102C polymorphism is associated with maintenance, but not with initiation of the smoking habit. The CC genotype was more frequent in the current smokers than in the never + former smokers (chi(2) = 6.825, P = 0.03). The odds ratio of being a current smoker with a CC genotype was 1.63, 95% CI 1.06-2.51.     

Association analysis of 5-HTTLPR variants, 5-HT2a receptor gene 102T/C polymorphism and migraine

It is well known that migraine has a strong genetic component, although the type and number of genes involved is not yet clear. There is evidence to suggest that serotonin-related genes participate in the pathogenesis of migraine. Previous studies have shown that gender differences influence the serotonergic neurotransmission and, in addition, the migraine prevalence is higher in females than males. Therefore, we investigated the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the 102T/C polymorphism of the 5-HT2A receptor gene in the Hungarian female population. These genes were analysed in 126 migraine sufferers (with or without aura)and 101 unrelated healthy controls using case control design. A borderline association (chi2 = 3.84, df = 1, p = 0.049; OR = 1.45, 95% CI = 1.00-2.12) between 5-HTTLPR short (S) allele and migraine was found. No significant difference between migraine sufferers and controls was observed for the 102T/C polymorphism of 5-HT2A receptor gene. Furthermore, there was no significant interaction between5-HTTLPR and 102T/C polymorphisms in our study population. In conclusion, our results support that the genetic susceptibility of migraine may be associated with a locus at or near the 5-HT transporter gene.     

多巴胺受体D2型基因启动区多态性与精神分裂症关联研究

目的探讨湖北武汉地区汉族人群中多巴胺受体D2型基因(dopamine receptor D2, DRD2)启动区-141位点胞嘧啶插入/缺失多态性与精神分裂症的关联关系.方法应用聚合酶链反应-限制性片段长度多态性方法,对120例精神分裂症患者、100名健康对照者进行基因分型.对精神分裂症患者的 DRD2 -141位点胞嘧啶插入/缺失多态性进行了相关分析.结果 DRD2型基因启动区-141位点的等位基因、基因型频率在精神分裂症组与对照组之间的分布差异有统计学意义(P<0.05).在精神分裂症组中,-141C缺失的等位基因频率为0.11,对照组为0.18(比值比为0.55,95%可信区间为0.30～0.96,P <0.05).结论 -141位点胞嘧啶插入/缺失多态性非独立性地对精神分裂症与 DRD2基因的相关性产生修饰作用.-141位点胞嘧啶缺失可能是湖北武汉汉族精神分裂症患者的保护因素之一.     

Distribution of the serotonin 2C (5HT2C) receptor gene -759C/T polymorphism in patients with schizophrenia and normal controls

BACKGROUND: In patients with schizophrenia, the percentage of patients with diabetes has been found to be twice that of the normal population. The risk factors for this higher rate are unknown, although dietary, lifestyle, and genetic factors have all been suggested. Recently, a polymorphism (-759C/T) in the serotonin 2C (5HT2C) receptor promoter region has been associated with the development of diabetes in a normal control population, with the frequency of the T allele being higher in subjects without diabetes. AIM: To determine whether the distribution of the -759C/T polymorphism of the 5HT2C receptor is different among patients with schizophrenia and normal controls. METHODS: DNA from 100 patients with schizophrenia and 81 normal controls were analyzed for the 5HT2C receptor -759C/T polymorphism to determine its allelic frequencies in these two groups. RESULTS: Using a chi-squared analysis, no statistical differences in the distribution of C alleles and T alleles were found between the two groups (P=0.2931). CONCLUSIONS: Patients with schizophrenia have a higher risk for developing diabetes than the general population. We did not find a higher distribution of the -759T allele of the 5HT2C receptor in normal controls compared with in patients with schizophrenia. This suggests the higher prevalence of diabetes in schizophrenia is not due to this polymorphism.     

Clozapine-induced weight gain associated with the 5HT2C receptor -759C/T polymorphism.

Weight gain has been documented as a significant adverse effect associated with many of the atypical antipsychotic medications. Several recent reports have linked a -759C/T polymorphism of the 5HT2C receptor gene and obesity as well as chlorpromazine, risperidone, and clozapine induced to weight gain. This aim was to determine the association between changes in body mass index (BMI) during clozapine treatment and the -759C/T polymorphism of the 5HT2C receptor gene. This study included 41 patients with treatment-refractory schizophrenia (DSM-IV) who were followed prospectively during treatment with clozapine. Weight and height measurements were obtained prior to starting clozapine and after 6-months of treatment. Genomic DNA was isolated from a whole blood sample and analyzed for the -759C/T polymorphism of the 5HT2C receptor gene. A chi(2) analysis comparing whether or not the subjects carried a -759T allele in subjects grouped as having an increase of more or less than 7% of their baseline BMI during treatment with clozapine found that the presence of the -759T allele was significantly higher in subjects with less than or equal to a 7% increase in baseline BMI compared to those with a greater than 7% increase in BMI. A multiple linear regression analysis showed that both baseline BMI and the presence or absence of the -759T allele had significant effects on 6-month BMI. The T allele may have a protective function in preventing significant weight gain from clozapine. Subjects without the -759T variant allele were at a greater risk for weight gain from clozapine over 6-months compared to those with the -759T allele.     

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.     

Cultural consonance,a 5HT2A receptor polymorphism,and depressive symptoms: A longitudinal study of gene × culture interaction in urban Brazil

In this study in urban Brazil we examine, as a predictor of depressive symptoms, the interaction between a single nucleotide polymorphism in the 2A receptor in the serotonin system (?1438G/A) and cultural consonance in family life, a measure of the degree to which an individual perceives her family as corresponding to a widely shared cultural model of the prototypical family. A community sample of 144 adults was followed over a 2‐year‐period. Cultural consonance in family life was assessed by linking individuals' perceptions of their own families with a shared cultural model of the family derived from cultural consensus analysis. The ?1438G/A polymorphism in the 2A serotonin receptor was genotyped using a standard protocol for DNA extracted from leukocytes. Covariates included age, sex, socioeconomic status, and stressful life events. Cultural consonance in family life was prospectively associated with depressive symptoms. In addition, the interaction between genotype and cultural consonance in family life was significant. For individuals with the A/A variant of the ?1438G/A polymorphism of the 2A receptor gene, the effect of cultural consonance in family life on depressive symptoms over a 2‐year‐period was larger (β = ?0.533, P < 0.01) than those effects for individuals with either the G/A (β = ?0.280, P < 0.10) or G/G (β = ?0.272, P < 0.05) variants. These results are consistent with a process in which genotype moderates the effects of culturally meaningful social experience on depressive symptoms. Am. J. Hum. Biol., 2009. © 2008 Wiley‐Liss, Inc.     

The 5-HT(2A) receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed patients.

Several lines of evidence suggest that genetic factors constitute an important determinant of suicidal behavior. A significant association between the 5-HT(2A)-C allele and suicidality has recently been reported. The aim of this study was to investigate whether the proposed association between 5-HT(2A)-102T/C polymorphism and suicidality could be replicated in a larger and independent sample of Spanish patients with major depression. The 102T/C polymorphism of the 5-HT(2A) receptor gene was analyzed in 159 patients with major depression (DSM-IV criteria) and 164 unrelated and healthy controls using a case control design. All individuals were subjects of Spanish origin. Significant differences in allele (chi-square = 4.13, df = 1, P = 0.04) and genotype (chi-square = 6.19, df = 2, P = 0.04) distributions were found between non-suicide attempters and suicide attempters. Moreover, those patients carrying 5-HT(2A)-C allele had more than five times the risk for attempting suicide than noncarriers (OR = 5.50, 95% CI = 1.18-35.20, P = 0.01). Our results replicate the proposed association between 5HT(2A)-C allele and suicidality in major depression. Moreover, no overall associations are detected when patients with major depression and controls are compared for 102T/C frequencies, suggesting that the increased risk for suicidality conferred by 5-HT(2A)-C allele is primarily associated with suicidal behavior and not with the diagnosis of major depression itself.