Perinatal antibiotics exposure causes increase in serum 5-hydroxytryptamine level as well as changes in behavior and gastrointestinal motility in the male offspring in mice / 生理学报

The current study was aimed to investigate the potential effects of perinatal exposure to therapeutic dose of penicillin and cefixime on the cognitive behaviors, gastrointestinal (GI) motility and serum 5-hydroxytryptamine (5-HT) level in the offspring. Pregnant rats were continuously treated with cefixime or penicillin in the period between 1 week before and 1 week after labor. Behavior tests, including social preference, self-grooming and elevated plus maze tests, and intestinal motility tests were carried out on the offspring at age of 4 to 10 weeks. Serum 5-HT levels were detected with ELISA, and potassium/sodium hyperpolarization activated cyclic nucleotide-gated channel 2 (HCN2) and tryptophan hydroxylase 1 (TPH1) expression levels in colon epithelium of offspring were detected by Western blot and RT-qPCR. The results showed that, compared with the naive group, cefixime increased social behavior in the female offspring, but did not affect the male offspring. Compared with the naive group, cefixime significantly decreased colonic and intestinal transits, and increased cecum net weight and standardized cecum net weight in the male offspring, but did not affect the female offspring. The serum 5-HT levels in the male offspring, rather than the female offspring, in cefixime and penicillin groups were significantly increased compared with that in the naive group. The protein expression level of HCN2 in colon epithelium of the offspring in cefixime group was significantly down-regulated, and the TPH1 expression level was not significantly changed, compared with that in the naive group. These results suggest that perinatal antibiotics exposure may affect neural development and GI functions of the offspring, and the mechanism may involve peripheral 5-HT and gender-dependent factor.

Cloning and expression characteristics of tryptophan hydroxylase (TRH) from silkworm, Bombyx mori / 生物工程学报

The biogenic monoamine 5-hydroxytryptamine (5-HT) is an ancient intracellular signaling molecule widely distributed in all animals with nervous systems, and has been implicated in principal behaviors. Tryptophan hydroxylase (TRH) induces a highly specific catalytic reaction that converts L-tryptophan (tryptophan) to 5-hydroxy-L-tryptophan (5-HTP) that is subsequently used as a substrate by aromatic L-amino acid decarboxylase (DDC) to form 5-HT. Five-HT is an ancient intracellular signaling molecule that is widely distributed in the animal kingdom and has been implicated in regulating the behaviors of animals with nervous systems. However, the role of TRH in Lepidoptera is not well understood. In this study, we cloned 1 667 bp cDNAs of Bombyx mori TRH (BmTRH), which contains a 1 632 bp open reading frame (ORF). Homology analysis revealed that BmTRH shared high amino acid identity with Homo sapiens TPH and Drosophila TRH (DmTRH). The high homology (70%) of BmTRH with DmTRH suggested that BmTRH could have a function similar to DmTRH. Gene expression analysis revealed that BmTRH was mainly expressed in head and central nervous (CNS). Moreover, immunohistochemistry and Western blotting analyses showed that BmTRH was detected only in larval nervous tissues. Taken together, our results indicate that BmTRH could likely function in the regulation of neural activities in B. mori. The transcripts of B. mori decarboxylase (BmDDC) and B. mori phenylalanine hydroxylase (BmPAH) whose proteins had TRH activity, were also expressed in the CNS tissues, indicating that unlike in Drosophila, two distinct mechanisms likely regulate 5-HT synthesis in silkworm.

Gene Expression Profiling and Assessment of Vitamin D and Serotonin Pathway Variations in Patients With Irritable Bowel Syndrome

BACKGROUND/AIMS: Irritable bowel syndrome (IBS) is a multifaceted disorder that afflicts millions of individuals worldwide. IBS is currently diagnosed based on the presence/duration of symptoms and systematic exclusion of other conditions. A more direct manner to identify IBS is needed to reduce healthcare costs and the time required for accurate diagnosis. The overarching objective of this work is to identify gene expression-based biological signatures and biomarkers of IBS. METHODS: Gene transcripts from 24 tissue biopsy samples were hybridized to microarrays for gene expression profiling. A combination of multiple statistical analyses was utilized to narrow the raw microarray data to the top 200 differentially expressed genes between IBS versus control subjects. In addition, quantitative polymerase chain reaction was employed for validation of the DNA microarray data. Gene ontology/pathway enrichment analysis was performed to investigate gene expression patterns in biochemical pathways. Finally, since vitamin D has been shown to modulate serotonin production in some models, the relationship between serum vitamin D and IBS was investigated via 25-hydroxyvitamin D (25[OH]D) chemiluminescence immunoassay. RESULTS: A total of 858 genetic features were identified with differential expression levels between IBS and asymptomatic populations. Gene ontology enrichment analysis revealed the serotonergic pathway as most prevalent among the differentially expressed genes. Further analysis via real-time polymerase chain reaction suggested that IBS patient-derived RNA exhibited lower levels of tryptophan hydroxylase-1 expression, the enzyme that catalyzes the rate-limiting step in serotonin biosynthesis. Finally, mean values for 25(OH)D were lower in IBS patients relative to non-IBS controls. CONCLUSIONS: Values for serum 25(OH)D concentrations exhibited a trend towards lower vitamin D levels within the IBS cohort. In addition, the expression of select IBS genetic biomarkers, including tryptophan hydroxylase 1, was modulated by vitamin D. Strikingly, the direction of gene regulation elicited by vitamin D in colonic cells is “opposite” to the gene expression profile observed in IBS patients, suggesting that vitamin D may help “reverse” the pathological direction of biomarker gene expression in IBS. Thus, our results intimate that IBS pathogenesis and pathophysiology may involve dysregulated serotonin production and/or vitamin D insufficiency.

Dexmedetomidine Ameliorates Sleep Deprivation-Induced Depressive Behaviors in Mice / 대한배뇨장애요실금학회지

PURPOSE: Sleep deprivation induces depressive symptoms. Dexmedetomidine is a α2-adrenoreceptor agonist and this drug possesses sedative, anxiolytic, analgesic, and anesthetic-sparing effect. In this study, the action of dexmedetomidine on sleep deprivation-induced depressive behaviors was investigated using mice. METHODS: For the inducing of sleep deprivation, the mice were placed inside a water cage containing 15 platforms and filled with water up to 1 cm below the platform surface for 7 days. One day after sleep deprivation, dexmedetomidine at the respective dosage (0.5, 1, and 2 μg/kg) was intraperitoneally treated into the mice, one time per a day during 6 days. Then, forced swimming test and tail suspension test were conducted. Immunohistochemistry for tyrosine hydroxylase (TH), 5-hydroxytryptamine (5-HT; serotonin), tryptophan hydroxylase (TPH) and western blot for D1 dopamine receptor were also performed. RESULTS: Sleep deprivation increased the immobility latency in the forced swimming test and tail suspension test. The expressions of TPH, 5-HT, and D1 dopamine receptor were decreased, whereas, TH expression was increased by sleep deprivation. Dexmedetomidine decreased the immobility latency and increased the expressions of TPH, 5-HT, and D1 dopamine receptor, whereas, HT expression was decreased by dexmedetomidine treatment. CONCLUSIONS: In our results, dexmedetomidine alleviated sleep deprivation-induced depressive behaviors by increasing 5-HT synthesis and by decreasing dopamine production with up-regulation of D1 dopamine receptor.

Characterisation of three polymorphisms of the tryptophan hydroxylase 2 gene in a sample of Colombian population with major depressive disorder / Caracterización de tres polimorfismos del gen de la triptófano hidroxilasa 2 en una muestra de población colombiana con trastorno depresivo mayor

ABSTRACT Objective: Identify whether rs11179000, rs136494 and rs4570625 polymorphisms of the tryptophan hydroxylase 2 gene, are associated with a major depressive disorder in a sample of the Colombian population. Methods: Case-control study was conducted in which a comparison was made between subjects diagnosed with major depressive disorder at some point in adulthood or active symptoms at the time of evaluation, and subjects with no psychiatric disease. Subjects were studied in the Department of Psychiatry, Faculty of Medicine and the Institute of Genetics at the National University of Colombia. Polymorphisms were genotyped using Taqman probes in real time PCR. As well as studying the association between major depressive disorder and these single nucleotide polymorphisms (SNPs), the association with other factors previously associated with depression were also analysed. Results: No statistically significant association between genotypic and allelic frequencies of each polymorphism and major depressive disorder was found. Association between sex and complication during pregnancy/childbirth and major depressive disorder was observed. Association between sex and complication during pregnancy/childbirth and major depres sive disorder was observed. Conclusions: There was no association between any polymorphism and major depressive disorder.

RESUMEN Objetivo: Identificar si los polimorfismos rs11179000, rs136494 y rs4570625 del gen de la triptófano hidroxilasa 2 están asociados a trastorno depresivo mayor en una muestra de población colombiana. Métodos: Estudio de casos y controles en el que se comparó a sujetos con trastorno depresivo mayor diagnosticado en algún momento de la vida adulta o con síntomas activos en el momento de la valoración y sujetos sin enfermedad psiquiátrica. Se estudió a los sujetos en el Departamento de Psiquiatría de la Facultad de Medicina y en el Instituto de Genética de la Universidad Nacional de Colombia. Se genotipificaron los polimorfismos usando reacción en cadena de la polimerasa en tiempo real y sondas Taqman. Además de buscar asociación entre trastorno depresivo mayor y estos polimorfismos de un solo nucleótido, se exploró asociación con otros factores relacionados previamente con depresión. Resultados: No se encontró asociación estadísticamente significativa entre las frecuencias genotípicas o alélicas de cada polimorfismo y el trastorno depresivo mayor. Se observó asociación entre sexo y complicaciones durante el embarazo/parto y trastorno depresivo mayor. Conclusiones: No se halló asociación entre polimorfismo alguno y el trastorno depresivo mayor.

Serotonin as a New Therapeutic Target for Diabetes Mellitus and Obesity

Serotonin (5-hydroxytryptamine [5-HT]) is a monoamine that has various functions in both neuronal and non-neuronal systems. In the central nervous system, 5-HT regulates mood and feeding behaviors as a neurotransmitter. Thus, there have been many trials aimed at increasing the activity of 5-HT in the central nervous system, and some of the developed methods are already used in the clinical setting as anti-obesity drugs. Unfortunately, some drugs were withdrawn due to the development of unwanted peripheral side effects, such as valvular heart disease and pulmonary hypertension. Recent studies revealed that peripheral 5-HT plays an important role in metabolic regulation in peripheral tissues, where it suppresses adaptive thermogenesis in brown adipose tissue. Inhibition of 5-HT synthesis reduced the weight gain and improved the metabolic dysfunction in a diet-induced obesity mouse model. Genome-wide association studies also revealed genetic associations between the serotonergic system and obesity. Several genetic polymorphisms in tryptophan hydroxylase and 5-HT receptors were shown to have strong associations with obesity. These results support the clinical significance of the peripheral serotonergic system as a therapeutic target for obesity and diabetes.

Stress-Induced Depression Is Alleviated by Aerobic Exercise Through Up-Regulation of 5-Hydroxytryptamine 1A Receptors in Rats / 대한배뇨장애요실금학회지

PURPOSE: Stress is associated with depression, which induces many psychiatric disorders. Serotonin, also known as 5-hydroxy-tryptamine (5-HT), acts as a biochemical messenger and regulator in the brain. It also mediates several important physiological functions. Depression is closely associated with an overactive bladder. In the present study, we investigated the effect of treadmill exercise on stress-induced depression while focusing on the expression of 5-HT 1A (5-H(1A)) receptors in the dorsal raphe. METHODS: Stress was induced by applying a 0.2-mA electric foot shock to rats. Each set of electric foot shocks comprised a 6-second shock duration that was repeated 10 times with a 30-second interval. Three sets of electric foot shocks were applied each day for 7 days. For the confirmation of depressive state, a forced swimming test was performed. To visualize the expression of 5-HT and tryptophan hydroxylase (TPH), immunohistochemistry for 5-HT and TPH in the dorsal raphe was performed. Expression of 5-H(1A) receptors was determined by western blot analysis. RESULTS: A depressive state was induced by stress, and treadmill exercise alleviated the depression symptoms in the stress-induced rats. Expressions of 5-HT, TPH, and HT 1A in the dorsal raphe were reduced by the induction of stress. Treadmill exercise increased 5-HT, TPH, and HT 1A expressions in the stress-induced rats. CONCLUSIONS: Treadmill exercise enhanced 5-HT synthesis through the up-regulation of 5-HT(1A) receptors, and improved the stress-induced depression. In the present study, treadmill exercise improved depression symptoms by enhancing 5-HT(1A) receptor expression. The present results suggest that treadmill exercise might be helpful for the alleviation of overactive bladder and improve sexual function.

Involvement of miR-30c in resistance to doxorubicin by regulating YWHAZ in breast cancer cells

MicroRNAs (miRNAs) are small RNA molecules that modulate gene expression implicated in cancer, which play crucial roles in diverse biological processes, such as development, differentiation, apoptosis, and proliferation. The aim of this study was to investigate whether miR-30c mediated the resistance of breast cancer cells to the chemotherapeutic agent doxorubicin (ADR) by targeting tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ). miR-30c was downregulated in the doxorubicin-resistant human breast cancer cell lines MCF-7/ADR and MDA-MB-231/ADR compared with their parental MCF-7 and MDA-MB-231 cell lines, respectively. Furthermore, we observed that transfection of an miR-30c mimic significantly suppressed the ability of MCF-7/ADR to resist doxorubicin. Moreover, the anti-apoptotic gene YWHAZ was confirmed as a target of miR-30c by luciferase reporter assay, and further studies indicated that the mechanism for miR-30c on the sensitivity of breast cancer cells involved YWHAZ and its downstream p38 mitogen-activated protein kinase (p38MAPK) pathway. Together, our findings provided evidence that miR-30c was one of the important miRNAs in doxorubicin resistance by regulating YWHAZ in the breast cancer cell line MCF-7/ADR.

Age related interaction of dopamine and serotonin synthesis in striatal synaptosomes

Tyrosine hydroxylase and tryptophan hydroxylase are key rate limiting enzymes in the biosynthesis of dopamine and serotonin, respectively. Since both enzymes are active in striatum, and affected by age, this study was undertaken to investigate interaction between dopamine and serotonin synthesis in brain striatal synaptosomes of aging rat. Male Wistar rats (3 and 30 month old) were killed by decapitation and brain striatal synaptosomes were prepared by discontinuous Ficoll/sucrose gradient technique. Synaptosomes were incubated in the presence of added pargiline (monoamineoxidase inhibitor), dopamine or serotonin synthesized during 25 min was measured by HPLC, employing electrochemical detection. Dopamine synthesis in synaptosomes prepared from young animals was markedly inhibited by addition of 5 microM serotonin concentrations (30%) and increasing serotonin concentrations up to 50 microM caused only a smaller additional inhibition. Dopamine synthesis in synaptosomes obtained from old rats was significantly lower than that of youg animals and addition of serotonin concentrations up to 50 microM had little effect on these preparations. In case of serotonin synthesis, exogenously added 5 microM dopamine inhibited serotonin synthesis in the synaptosomes of both ages by about 40%, whereas with higher concentration of dopamine (10-50 microM) the rate of inhibition was highly pronounced in old rats as compared to that of young animals. It is concluded that dopamine and serotonin interaction may be significant, and that these should be considered in long-term treatments of Parkinson's disease with L-DOPA.

Genetic polymorphisms of SNP loci in the 5' and 3' region of TPH2 gene in Northern Chinese Han population / 法医学杂志

OBJECTIVE@#To investigate the genetic polymorphism in the 5' and 3' region of TPH2 gene of Northern Chinese Han population and to explore its application value in forensic medicine.@*METHODS@#The sequence variants and the genetic polymorphisms of 6 SNP loci (rs4570625, rs11178997, rs11178998, rs41317118, rs17110747 and rs41317114) within a 905 bp 5' flanking region and a 1,104bp 3' flanking region of TPH2 gene were analyzed by DNA sequencing in a total of 244 unrelated healthy individuals in Northern Chinese Han population. The statistical analysis was carried out by Haploview v4.2 software.@*RESULTS@#The genotypic distributions of the 6 SNP loci in the TPH2 gene were in accordance with Hardy-Weinberg equilibrium. One C/T variant in 92922 site was found. There was a high linkage disequilibrium among the 3 SNP loci (rs4570625, rs11178997 and rs11178998) in the 5' region and the 3 SNP loci (rs41317118, rs17110747 and rs41317114) in the 3' region of TPH2 gene, respectively. The parameters of population genetics of 6 SNP loci were obtained.@*CONCLUSION@#There are great polymorphisms in the 5' and 3' region of TPH2 gene in Northern Chinese Han population, which could be used as genetic indexes for association analysis of the related diseases, as well as for forensic individual identification and paternity testing.

Relationship between Sleep, Suicide, and Serotonin / 수면정신생리

One of hypothesis is that sleep loss related to a decrease in serotonergic activity plays a significant role in attempted suicide. A growing evidence suggests that central serotonergic activity plays a key role in the etiology of suicide. It has been reported that the cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, were reduced in suicide attempters. In addition, there is evidence that tryptophan hydroxylase is associated with suicide. The association between sleep and suicide was also suggested by some researchers. Several recent studies have showed the association between sleep disturbance and suicide rates in patients with mental disorders and in a general population. In addition, it has been suggested that serotonin plays a role in maintaining arousal and regulating muscle tone and in regulating some of the phasic events of REM sleep. Especially, it is well-known that 5-HT2 receptors are related to slow wave sleep. In conclusion, it is clear that sleep, serotonin activity, and suicide are linked, although the direction of causation needs clarification. In future, large population-based cohort studies are needed to demonstrate the direction of causation in the relationships between sleep, serotonin activity, and suicide.

New Avenues in the LRP5-mediated Bone Mass Acquisition

Lipoprotein receptor-related protein (LRP5) signaling is well correlated with the bone mass in both human and mice. Loss-of-function mutations of LRP5 result in osteopenia or osteoporosis. In contrast, gain-of-function mutations show high bone mass phenotype. To elucidate the molecular mechanism of the LRP5-mediated bone mass acquisition, several groups have genetically dissected the Wingless and Int-1 (Wnt)beta-catenin signaling pathway using osteoblast-lineage specific Cre mice. Key players for LRP5-mediated bone mass acquisition turn out to be different molecules with respect to the expressing tissue and action mode of these molecules. One is serotonin, a tryptophan metabolite that originates from duodenum, which acts as a negative regulator for bone formation. LRP5 suppresses serotonin biosynthesis by inhibiting the expression of tryptophan hydroxylase 1 in the gut. The other is sclerostin, an osteocyte-producing antagonist for LRP5 signaling. Here is a summary of recent findings about these two molecules, providing a chance to speculate new avenues in the LRP5-mediated bone mass acquisition.

New Avenues in the LRP5-mediated Bone Mass Acquisition

Lipoprotein receptor-related protein (LRP5) signaling is well correlated with the bone mass in both human and mice. Loss-of-function mutations of LRP5 result in osteopenia or osteoporosis. In contrast, gain-of-function mutations show high bone mass phenotype. To elucidate the molecular mechanism of the LRP5-mediated bone mass acquisition, several groups have genetically dissected the Wingless and Int-1 (Wnt)beta-catenin signaling pathway using osteoblast-lineage specific Cre mice. Key players for LRP5-mediated bone mass acquisition turn out to be different molecules with respect to the expressing tissue and action mode of these molecules. One is serotonin, a tryptophan metabolite that originates from duodenum, which acts as a negative regulator for bone formation. LRP5 suppresses serotonin biosynthesis by inhibiting the expression of tryptophan hydroxylase 1 in the gut. The other is sclerostin, an osteocyte-producing antagonist for LRP5 signaling. Here is a summary of recent findings about these two molecules, providing a chance to speculate new avenues in the LRP5-mediated bone mass acquisition.

Association Study between Tryptophan Hydroxylase 2 Gene -703G/T Polymorphism and Tardive Dyskinesia / 대한정신분열병학회지

OBJECTIVES: Tardive dyskinesia (TD) is a serious and sometimes irreversible adverse effect that may develop during long-term antipsychotics treatment. Previous studies have suggested that brain serotonergic systems are related to TD vulnerability and tryptophan hydroxylase (TPH) is the rate limiting enzyme in the biosynthesis of serotonin. This study aimed to investigate the association between TPH2 gene -703G/T polymorphism (rs4570625) and antipsychotic-induced TD in the Korean schizophrenia patients. METHODS: We investigated whether TPH2 gene -703G/T polymorphism is associated with antipsychotic-induced TD in 280 Korean schizophrenia patients. The subjects with TD (n=105) and without TD (n=175) were matched for antipsychotic drug exposure and other relevant variables. RESULTS: There was no significant difference in the distribution of genotypic (chi2=3.00, p=0.223) and allelic (chi2=0.19, p=0.661) frequencies between patients group with TD and without TD. There was no significant difference in total Abnormal Involuntary Movement Scale score (F=1.95, p=0.362) among the genotype groups, either. CONCLUSIONS: The present study does not support that TPH2 gene -703G/T polymorphism is involved in TD of the Korean schizophrenia subjects.

Association Study between Tryptophan Hydroxylase 2 Gene -703G/T Polymorphism and Tardive Dyskinesia / 대한정신분열병학회지

OBJECTIVES: Tardive dyskinesia (TD) is a serious and sometimes irreversible adverse effect that may develop during long-term antipsychotics treatment. Previous studies have suggested that brain serotonergic systems are related to TD vulnerability and tryptophan hydroxylase (TPH) is the rate limiting enzyme in the biosynthesis of serotonin. This study aimed to investigate the association between TPH2 gene -703G/T polymorphism (rs4570625) and antipsychotic-induced TD in the Korean schizophrenia patients. METHODS: We investigated whether TPH2 gene -703G/T polymorphism is associated with antipsychotic-induced TD in 280 Korean schizophrenia patients. The subjects with TD (n=105) and without TD (n=175) were matched for antipsychotic drug exposure and other relevant variables. RESULTS: There was no significant difference in the distribution of genotypic (chi2=3.00, p=0.223) and allelic (chi2=0.19, p=0.661) frequencies between patients group with TD and without TD. There was no significant difference in total Abnormal Involuntary Movement Scale score (F=1.95, p=0.362) among the genotype groups, either. CONCLUSIONS: The present study does not support that TPH2 gene -703G/T polymorphism is involved in TD of the Korean schizophrenia subjects.

Associations between polymorphic variants of the tryptophan hydroxylase 2 gene and obsessive-compulsive disorder / Associação entre polimorfismos do gene da triptofano hidroxilase 2 e o transtorno obsessivo-compulsivo

OBJECTIVE: A substantial body of evidence suggests that obsessive-compulsive disorder has a genetic component, and substantial candidate genes for the disorder have been investigated through association analyses. A particular emphasis has been placed on genes related to the serotonergic system, which is likely to play an important role in the pathogenesis of obsessive-compulsive disorder. The gene for tryptophan hydroxylase 2, which is a rate limiting enzyme in serotonin synthesis, is considered an important candidate gene associated with psychiatric disorders. METHOD: Our sample consisted of 321 subjects (107 diagnosed with obsessive-compulsive disorder and 214 healthy controls), which were genotyped for eight tagSNPs (rs4448731, rs4565946, rs11179000, rs7955501, rs10506645, rs4760820, rs1487275 and rs10879357) covering the entire human tryptophan hydroxylase 2 gene. Statistical analyses were performed using UNPHASED, version 3.0.12, and Haploview®. RESULTS: Single markers, genotype analysis did not show a significant genetic association with obsessive-compulsive disorder. A significant association between the T-C-T (rs4448731, rs4565946, rs10506645) and C-A-T (rs4565946, rs7955501, rs10506645) haplotypes and obsessive-compulsive disorder was observed, as well as a strong linkage disequilibrium between SNPs rs4448731 and rs4565946, and SNPs rs10506645 and 4760820. DISCUSSION: Our research has not demonstrated the existence of associations between the eight SNPs of TPH2 and obsessive-compulsive disorder. However, two LD and two haplotypes areas were demonstrated, thus suggesting that more studies in TPH2 are needed to investigate the role of tryptophan hydroxylase 2 variants in obsessive-compulsive disorder.

OBJETIVO: Diversos estudos demonstram que o transtorno obsessivo-compulsivo apresenta considerável contribuição genética, com diversos genes candidatos tendo sido estudados por meio de estudos de associação. Como alterações do sistema serotonérgico estão associadas ao transtorno obsessivo-compulsivo, o gene da triptofano hidroxilase 2, enzima limitante da síntese da serotonina, é plausível candidato para estudos. MÉTODO: Nossa amostra é composta de 321 sujeitos (107 pacientes com transtorno obsessivo-compulsivo e 214 controles) e investigamos oito tagSNPs (rs4448731, rs4565946, rs11179000, rs7955501, rs10506645, rs4760820, rs1487275 e rs10879357) do gene da triptofano hidroxilase 2. Análise estatística foi realizada com os programas UNPHASED e Haploview. RESULTADOS: Análise de frequência alélica e genotípica entre casos e controles não evidenciaram diferenças estatisticamente significativas. No entanto, observamos maior prevalência dos haplótipos T-C-T (rs4448731, rs4565946, rs10506645) e C-A-T (rs4565946, rs7955501, rs10506645) entre os pacientes, assim como duas regiões com importantes desequilíbrios de ligação (SNPs rs4448731 e rs4565946; SNPs rs10506645 e 4760820). DISCUSSÃO: Nossos achados não demonstraram uma associação entre os SNPs do gene da TPH2 e o transtorno obsessivo-compulsivo, porém mais estudos são necessários, já que fortes desequilíbrios de ligação foram demonstrados, assim como dois haplótipos.

Suicide : Gene-Environment Interaction

Gene-environment interactions are important in pathogenesis of suicide or suicidal behavior. Twin and adoption studies and family studies show that genetic factors play a critical role in suicide or suicidal behavior. Given the strong association between serotonergic neurotransmission and suicide, recent molecular genetic studies have focused on polymorphisms of serotonin genes, especially on serotonin transporter and tryptophan hydroxylase genes. Some studies have revealed a significant interaction between s allele of the serotonin transporter gene and the risk of suicide attempt associated with childhood trauma. In addition, the polymorphism of brain-derived neurotrophic factor gene also may influence the effect of childhood trauma in relation to the risk of attempting suicide. Future studies should explore genetic and environmental factors in suicide or suicidal behavior and examine for gene and environment interaction.

The Genetic Factors Affecting Drinking Behaviors of Korean Young Adults with Variant Aldehyde Dehydrogenase 2 Genotype

OBJECTIVE: We determined whether aldehyde dehydrogenase 2 (ALDH2) activity alters the way in which drinking behaviors are affected by gene polymorphisms of other alcohol-metabolizing enzymes and serotonin-related proteins. METHODS: Through a follow-up survey with a cohort comprising 551 university freshmen over a period of 6 years, we examined the genetic factors affecting drinking behaviors. In 2000, drinking behaviors were assessed and tryptophan hydroxylase (TPH) and ALDH2 gene polymorphisms were determined. Drinking behaviors were repeated in 2006 (n=150), and the gene polymorphisms of ADH1B, ADH1C, CYP2E1, 5-HTR2A 1438A/G, and 5-HTR2A IVS2 were also determined. RESULTS: In 2000, the variant and wild-type ALDH2 groups exhibited little difference in terms of drinking frequency and problem drinking. Furthermore, some genotypes influenced only the variant group: ADH1B*2/*2 was associated with a lower drinking frequency, and CYP2E1 c2 allele was associated with an increased risk of problem drinking. In 2006, drinking frequency and risk of problem drinking were significantly lower in the variant group than in the wild-type group. However, the TPH AA genotype disturbed that difference, meaning that the subjects in the variant group had developed a similar level of risk of problem drinking to that in the wild-type group. CONCLUSION: Korean university freshmen who were identified as a variant group drank as frequently as those in the wild-type group. For the subsequent 6 years they drank less frequently, thus decreasing the risk of problem drinking. However, that frequency drop was interrupted in those with gene polymorphisms such as ADH1B*1, CYP2E1 c2, and TPH A.

Association between Serotonin-Related Polymorphisms in 5HT2A, TPH1, TPH2 Genes and Bipolar Disorder in Korean Population

OBJECTIVE: The aim of the present study was to examine the association between serotonin-related gene polymorphisms and bipolar disorder in the Korean population. In addition, we sought to explore the relationship between the clinical characteristics of bipolar patients and serotonin-related gene polymorphisms. METHODS: Inpatients with bipolar disorder (n=103) and control subjects (n=86) were genotyped for 5HT2A 1438A/G, tryptophan hydroxylase 1 (TPH1) 218 A/C, and TPH2 703G/T. We divided patients with bipolar disorder into two groups according to the presence of psychotic symptoms. The severity of their symptoms was measured using the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS). RESULTS: There were no significant differences in the genotype distributions or allelic frequencies in the three serotonergic polymorphisms between patients with bipolar disorder and normal controls. There were significant differences in genotype distributions and allele frequencies of the 5-HT2A -1438A/G polymorphism between the psychotic mania group and the non-psychotic mania group (genotype: chi-square=7.50, p=0.024; allele: chi-square=5.92, p=0.015). However, after Bonferroni correction this signifact difference disappeared. We did not find significant differences in the genotype distributions or allelic frequencies in the TPH1 218 A/C and TPH2 703G/T polymorphisms between the psychotic mania group and non-psychotic mania group. CONCLUSION: We failed to found the statistically significant association between three polymorphisms and bipolar disorder. However, there was a trend towards association between 5-HT2A -1438A/G polymorphism and psychotic symptom in bipolar disorder. Future research should seek to clarify this association.

No Evidence of an Association between A218C Polymorphism of the Tryptophan Hydroxylase 1 Gene and Aggression in Schizophrenia in a Korean Population

PURPOSE: We investigated the association between the tryptohan hydroxylase 1 (TPH1) gene and aggression in schizophrenia in a Korean population. MATERIALS AND METHODS: The sample included 61 aggressive patients as well as 104 non-aggressive patients from psychiatric hospitals and 335 healthy volunteers in Korea. Blood samples were collected from all participants for TPH1 A218C genotyping. The patients were administered standard psychiatric interviews as well as a self-report questionnaire for anger-related traits. RESULTS: In the case-control phenotypic comparisons, there was no significant association between the aggressive patients and the TPH1 A218C polymorphism. There was no significant effect of the TPH1 genotype on the anger-related traits, or no significant interaction between the genotype and group (aggressive and non-aggressive patients). CONCLUSION: These findings suggest that TPH1 does not play a major role in aggressive behavior via anger in schizophrenic patients.