Tryptophan Hydroxylase Gene Polymorphism Research Articles

Tryptophan hydroxylase gene polymorphism in patients with obsessive-compulsive disorder

Objective: There is limited number of studies on the effects of tryptophan hydroxylase-1 (TPH-1) A218C gene polymorphism on obsessive-compulsive disorder (OCD) etiology. This study aims to scrutinize the role of TPH-1 A218C gene polymorphism on OCD etiology. Methodology: Sixty patients diagnosed with OCD, applied to our clinic and fitting the study criteria were accepted as patient group. A group of 60 healthy individuals matching the patient group in age and gender were selected as the control group. In the study the Clinical Interview Scale Structured for DSM-IV Axis-I Disorders, Sociodemographic and Clinical Data Form, Yale-Brown Obsessive Compulsive Rating Scale (Y-BOCS) and Hamilton Depression Rating Scale were applied to participants initially. Consequently, they were classified into two groups of ‘responsive to therapy’ and ‘resistant to therapy’ based on their therapy histories and Y-BOCS points. For DNA isolation 300 μl blood samples were used in compliance with standard methods. Restriction Fragment Length Polymorphism method was used to evaluate A218C polymorphism in TPH-1 gene within the blood samples. Results: No significant difference was observed between patient and control groups related to TPH-1 genotypes. However, a significant increase was observed in AA genotype frequency for TPH-1 gene in the patient group resistant to therapy and in CC genotype frequency in the patient group responsive to therapy. The difference of the allele type ratios in this polymorphism between each patient group could be related to the response to therapy. To confirm the findings of the study, more research on the same gene polymorphisms is required with OCD patients in different societies.

TPH Gene Polymorphisms Are Associated With Disease Perception and Quality of Life in Women With Irritable Bowel Syndrome

The aims of this exploratory study were to examine whether tryptophan hydroxylase (TPH) gene polymorphisms are associated with psychosocial factors in women with irritable bowel syndrome (IBS). TPH is the rate-limiting enzyme in the biosynthesis of serotonin and has two isoforms, TPH1 and TPH2. Four single nucleotide polymorphisms (SNPs) in the TPH1 gene and one SNP in the TPH2 gene were selected based on previous studies investigating associations between these SNPs and psychiatric or behavioral disorders. One hundred ninety-nine Caucasian women with IBS were included. Results of univariate analysis showed no association between TPH1and TPH2 gene SNPs and current level of psychological distress or psychiatric illness. However, TPH1 gene SNPs were associated with IBS-related cognitions (rs4537731 and rs21105) and quality of life (rs684302 and rs1800532), in particular the mental health and energy subscales. These associations were independent of the subjects' levels of gastrointestinal symptoms. These results suggest that patients' perception of their illness, and of the impact it has on their lives, may be subject to genetic influences, in this case sequence variants in TPH1. However, caution should be used in interpreting these results given the large number of hypothesis tests performed in this exploratory hypothesis-generating study, and the results should be considered tentative until confirmed in an independent sample.

P.4.b.003 Tryptophan hydroxylase and serotonin transporter gene polymorphism does not affect the diagnosis and treatment outcome of panic disorder

Fatty acid amide hydrolase (FAAH) inhibitors are addressed for promising anxiolytics, but human studies on genetically reduced FAAH activity, stress and affective phenotypes are scarce. We investigated the effect of a functional polymorphism of FAAH (FAAH C385A or rs324420; low FAAH activity and high anandamide concentration are associated with the A allele) together with childhood adversity on the anxious and depressive phenotypes in 858 subjects from the general population. Phenotypes were measured by the Zung Self-Rating Depression Scale (ZSDS), the depression and anxiety subscales of the Brief Symptom Inventory (BSI-DEP, BSI-ANX) and the State-Trait Anxiety scales (STAI-S, STAI-T). Childhood Adversity Questionnaire (CHA) was used to assess early life traumas. Frequency of the A allele was greater among subjects with high ZSDS scores compared to the CC genotype. Furthermore, FAAH C385A and the CHA have shown a robust gene–environment interaction, namely, significantly higher anxiety and depression scores were exhibited by individuals carrying the A allele if they had high CHA scores compared to CC carriers. These data provided preliminary evidence that genetically reduced FAAH activity and repetitive stress in the childhood are associated with increased vulnerability for anxiety and depression in later life. Our results together with earlier experimental data suggest that permanently elevated anandamide level together with early life stress may cause a lifelong damage on stress response probably via the downregulation of CB1R during the neurodevelopment in the brain. It may also point to pharmacogenomic consequences, namely ineffectiveness or adverse effects of FAAH inhibitors in this subpopulation.

Effect of Tryptophan Hydroxylase Gene Polymorphism on Aggression in Major Depressive Disorder and Undifferentiated Somatoform Disorder

Aggression and anger have been linked with depression, and anger suppression has been linked with somatic symptoms of somatoform disorders. However, the relationship between aggression or anger and genes in patients with depression and somatoform disorders has not been clearly elucidated. The objective of this study was to examine the effect of serotonin-related gene polymorphism on aggression in depressive disorders and somatoform disorders. A serotonin-related polymorphic marker was assessed by using single nucleotide polymorphism (SNP) genotyping. 106 outpatients with major depressive disorder (MDD), 102 outpatients with undifferentiated somatoform disorder, and 133 healthy subjects were enrolled between October 2005 and May 2008. Diagnoses were made according to the Korean version of the Structured Clinical Interview Schedule for DSM-IV. The allele and genotype frequencies of tryptophan hydroxylase-1 (TPH1) A218C were compared between groups. The Hamilton Depression Rating Scale and the Aggression Questionnaire were used for psychological assessment. Each of the 2 disorder groups scored significantly higher on all the Aggression Questionnaire subscales and on the total Aggression Questionnaire score than the healthy subjects (P < .001). Patients with MDD had significantly higher frequencies of TPH1 C allele (P = .0002) and CC homozygote (P = .0003) than healthy subjects, regardless of sex and age. However, no significant differences were found in TPH1 C allele and CC homozygote frequencies between the undifferentiated somatoform disorder patients and the healthy subjects. TPH1 CC homozygote in the MDD group scored significantly higher in terms of verbal aggression (P = .03) and total Aggression Questionnaire score (P = .04) than A-carrier genotypes, regardless of sex and age. However, no significant differences were found in the scores of all the Aggression Questionnaire subscales and the total Aggression Questionnaire score between TPH1 CC homozygote and A-carrier genotypes in the undifferentiated somatoform disorder group and the control group, respectively. Aggression in MDD patients is more susceptible to an excess of TPH1 CC homozygote than in undifferentiated somatoform disorder patients, though the 2 disorders are high risk groups for aggression. In addition, TPH1 gene is most likely to have a shared effect on aggression and MDD.

Associations of tryptophan hydroxylase gene polymorphisms with irritable bowel syndrome

Background Alterations in serotonin (5-HT) are suspected in the pathophysiology of irritable bowel syndrome (IBS). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin and has two isoforms: TPH1 and TPH2. Genetic variants in both genes have been studied in various disorders related to serotonin dysregulation. The aim of this study was to examine whether TPH gene variants were associated with IBS and IBS-related gastrointestinal (GI) symptoms. Methods Five single nucleotide polymorphisms (SNPs) from the TPH1 and one SNP from the TPH2 were genotyped in 199 IBS patients and 79 healthy controls. All subjects were Caucasian women of European origin. Irritable bowel syndrome patients filled in a daily diary with five GI symptoms and stool characteristics for 28 days. Key Results The TPH1 SNPs showed no association with the diagnosis of IBS. However, among IBS patients, all five TPH1 SNPs showed some association with diarrhea and loose type of stool consistency, with P-values rating from 0.01 to 0.20. The TPH2 SNP showed a trend towards a reduced risk of IBS and possible associations with stool characteristics, both hard and loose stools. However, no P-values were less than the conservative multiple-comparison-adjusted threshold of 0.001 and hence these results must be interpreted cautiously. Conclusions & Inferences This study is the first to assess associations of TPH gene variants with IBS-related GI symptoms and stool characteristics. The possible association of TPH gene variants with diarrhea needs to be verified in an independent sample.

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

ObjectiveWe 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.MethodsThrough 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.ResultsIn 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.ConclusionKorean 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.

P.2.b.002 Association between two gene polymorphisms (SNPs) of tryptophan hydroxylase gene and suicidal behavior in depressive patients

P.2.b.002 Association between two gene polymorphisms (SNPs) of tryptophan hydroxylase gene and suicidal behavior in depressive patients

The A218C polymorphism of tryptophan hydroxylase gene and migraine

Objective To determine the significance of the A218C polymorphism of the tryptophan hydroxylase (TPH) gene in migraine. Methods Fifty-nine migraineurs and 62 healthy controls were included in the study, and polymerase chain reaction – restriction fragment length polymorphism assays were used to determine TPH A218C polymorphism. Results There was no association between TPH gene polymorphism and gender, family history of migraine and epilepsy, or aura. There was no significant difference between the allele frequencies of both groups ( p > 0.05). A significant difference was found between the genotypes of the migraineurs and controls regarding the AA genotype. Homozygosity for the C allele or heterozygosity for the A or C was not associated with the occurrence of migraine ( p > 0.05), but homozygosity for the A allele was less frequent in the migraineurs ( p = 0.02). Conclusion Since it is unlikely that TPH polymorphism alters serotonin biosynthesis, its association with migraine may be attributed to linkage disequilibrium with a functional variant within the TPH gene or a nearby gene.

Tryptophan hydroxylase and serotonin transporter gene polymorphism does not affect the diagnosis, clinical features and treatment outcome of panic disorder in the Korean population

Panic disorder may be associated with defective serotonin (5-HT) neurotransmission. This study was to investigate the association between the tryptophan hydroxylase (TPH) gene and a serotonin transporter gene promoter polymorphism (5-HTTLPR), with panic disorder in a Korean population. 244 Korean patients with panic disorder and the 227 controls were genotyped by a polymerase chain reaction-based method. The severity of panic disorders was assessed by number of panic attacks during the previous 1 month, as well as scores for anticipatory anxiety, panic distress, and agoraphobic distress, as determined by a visual analogue scale (VAS). All the subjects completed the assessment measures including Spielberger State-Trait Anxiety Inventory-State (STAI-S), Spielberger State-Trait Anxiety Inventory-Trait (STAI-T), Beck Depression Inventory (BDI), Symptom Checklist-90-Revised (SCL-90-R), Revised Anxiety Sensitivity Index (ASI-R), Clinical Global Impression Scale – Severity of Illness (CGI-S), Panic Disorder Severity Scale (PDSS), and the Hamilton Depression Rating Scale (HAMD). Responder analyses were conducted based on changes in CGI-I scores after 10 weeks of treatment. We found no significant differences in the genotype and allele frequencies in TPH A218C and 5-HTTLPR polymorphisms between the panic patients and the control group. Subgroup analyses in terms of comorbidities, response, and other primary clinical variables, indicated no differences in these polymorphisms. Our findings suggest that the TPH A218C polymorphism and 5-HTTLPR play no significant roles in the pathogenesis and clinical symptomatologies, at least in a Korean population.

Lack of association between the serotonin transporter and tryptophan hydroxylase gene polymorphisms and completed suicide

Lack of association between the serotonin transporter and tryptophan hydroxylase gene polymorphisms and completed suicide

Association between tryptophan hydroxylase gene polymorphisms and attention deficit hyperactivity disorder in Chinese Han population

Attention deficit hyperactivity disorder (ADHD) is a severe behavioral disorder in children known to have a substantial genetic component. Prior studies have implicated serotonin genes in the etiology of ADHD but have not examined tryptophan hydroxylase (TPH), which is a rate-limiting enzyme in serotonin biosynthesis. The current study examined the relationship between the A218C and A-6526G polymorphisms of the TPH gene and ADHD. Three hundred sixty-two unrelated ADHD probands and their biological parents were recruited to participate in this study. No biased transmission of any allele of the two polymorphisms was observed using TDT analysis. However, haplotype analyses found that the rare 218A/-6526G haplotype was significantly not transmitted to probands with ADHD (chi(2) = 4.4995, P = 0.034), regardless of subtype. Although this finding for ADHD in the Chinese Han population.

TPH gene polymorphism and aging: Indication of combined effect on the predisposition to violent suicide

Findings relating serotonin to suicidal behavior suggest the role of genes for tryptophan hydroxylase (TPH) in the genetic substrate of this disorder. Association of Tph1 gene and suicidality, despite considerable research efforts, remains controversial. Polymorphism A218C in intron 7 of Tph1 gene was studied in violent suicide victims (N = 247) and controls (N = 320) of Slavic (Croatian) origin, with specific consideration of the influence of subjects' age. The frequency of, allegedly less active, CC genotype was increased in older (above 65 years) victims as compared to controls (P = 0.0126 and 0.0008, for comparison with age-specific and integral control samples, respectively), while there were no differences between victims under 65 years and controls. Excess of the CC genotype in elderly victims of violent suicide points to the possible combined effect of the respective genetic factor and physiological changes during aging on the predisposition to this disorder.

No association between the tryptophan hydroxylase gene polymorphism and major depressive disorders and antidepressant response in a Korean population

The serotonergic neurotransmitter system has been implicated in major depressive disorder (MDD) and appears to be the target of a variety of antidepressants. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin biosynthesis, and selective serotonin re-uptake inhibitors exert their activity enhancing the general serotonergic tone. The goal of this study was to investigate whether the A218C polymorphism of the TPH gene is associated with MDD or antidepressant response. All patients were evaluated at the start and in the eighth week of using the 21-item Hamilton Depression Rating Scale. Genotyping was analyzed with polymerase chain reaction. There were no significant differences in genotypes and allele frequencies between the MDD patients (n = 93) and the control group (n = 127) and in the antidepressant response among TPH gene variants. Results suggest that the A218C polymorphism of the TPH gene does not play a major role in pathogenesis in MDD and does not serve as a modulator of antidepressant activity.

Monoamine oxidase A gene polymorphism and tryptophan hydroxylase gene polymorphism do not affect the antidepressant response to milnacipran in Japanese patients with major depressive disorder

Monoamine oxidase A gene polymorphism and tryptophan hydroxylase gene polymorphism do not affect the antidepressant response to milnacipran in Japanese patients with major depressive disorder

Tryptophan hydroxylase polymorphism is associated with age of onset of alcoholism related behaviors

The purpose of this study was to explore the association of a tryptophan hydroxylase gene polymorphism (TPH1 A218C) with the age of alcoholism onset in a Korean population. The genotype and allele frequencies of TPH1 were investigated in 182 male hospitalized patients who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for alcohol dependence. Alcoholics with the TPH1 AA or AC genotypes had an earlier age of disease onset (median age of onset, 26.5 years) than those with the CC genotype (median age of onset, 30 years; p = .002). Age of onset has been used in classifying alcoholics. The TPH1 polymorphism may explain, in part, the biological basis for these typologies.

Serotonin transporter and tryptophan hydroxylase gene polymorphisms in Chinese patients with generalized anxiety disorder

The serotonin transporter (5-HTT) and tryptophan hydroxylase (TPH) gene are important candidate genes for the psychiatric disorders. Many studies of patients with anxiety disorders have found abnormalities of serotonin metabolism and dysfunction of regulation in the transporter itself. In this study, we hypothesize that genetic variation in the 5-HTT and TPH gene may have an effect on the etiology of generalized anxiety disorder (GAD). Using a polymerase chain reaction-based technique, the allele and genotype frequencies of three polymorphisms in the serotonin transporter gene (a deletion/insertion polymorphism in the transcriptional control region and a variable number of tandem repeats in intron 2) and TPH gene (A218C in intron 7) were analyzed in 138 patients with GAD and 90 healthy controls. These two groups were matched for ethnic and geographic origin. The frequencies of 5-HTT gene-linked functional polymorphic region (5-HTTLPR) SS (short/short) genotype were significantly higher in GAD patients than in control subjects (68% versus 49%, chi = 12.274, df = 2, P = 0.002), and the frequencies of S (short) allele observed in the GAD patients were higher than those in healthy subjects (79 versus 71%, chi = 4.063, df = 1, P = 0.044). The odds ratio for the SS genotype versus the other two genotypes was 2.33 (95% confidence interval, 1.29-3.86). Similarly, the odds ratio for the S allele versus L allele was 1.56 (95% confidence interval, 1.01-2.41). The genotypic and allelic distribution of 5-HTT VNTR and TPH A218C polymorphisms did not show statistically significant differences between patients and controls. Our findings support that the presence of 5-HTTLPR-SS genotype may increase the risk of GAD.

Monoamine Oxidase A and Tryptophan Hydroxylase Gene Polymorphisms

Most of the candidate gene studies in bipolar disorder have focused on the major neurotransmitter systems that are influenced by drugs used in the treatment of this disorder. The monoamine oxidase A (MAOA) and the tryptophan hydroxylase (TPH1, TPH2) genes are two of the candidates that have been tested in a series of association studies using unrelated or family-based controls. This review summarizes the existing association studies regarding these genes. Most of these studies were based on the unrelated case-control design with samples of 50 to 600 subjects. Regarding MAOA, three meta-analyses with partially overlapping samples supported a modest effect of this gene in bipolar disorder in female Caucasians. However, as several studies could not replicate these findings, more work is necessary to demonstrate unequivocally the involvement of MAOA in bipolar disorder and establish the biological mechanism underlying the genetic association. With respect to TPH1 and TPH2, the majority of studies did not provide evidence for an association between these genes and bipolar disorder. The genes are more likely to be related to suicidal behavior than to bipolar disorder.

Association of tryptophan hydroxylase gene polymorphism with depression, anxiety and comorbid depression and anxiety in a population‐based sample of postpartum Taiwanese women

Depression and anxiety disorders often coexist clinically and both are known to have a genetic basis, but the mode of inheritance is too complicated to be determined so far. Serotonin is the biogenic amine neurotransmitter most commonly associated with depression and anxiety. Since tryptophan hydroxylase (TPH1) is the rate-limiting enzyme in serotonin biosynthesis, its role in the pathophysiology of these psychiatric diseases has been intensively studied. In this study, we examined whether polymorphism of the TPH1 gene is related to the etiology of major depression, anxiety and comorbid depression and anxiety. Five single nucleoside polymorphisms of the TPH1 gene were studied in a population-based sample of postpartum Taiwanese women consisting of 120 subjects with depression or/and anxiety and 86 matched normal controls. A significant difference (P = 0.0107) in genotype frequency for the T27224C polymorphism was found between the comorbid and normal groups, and risk analysis showed that the C allele conferred a strong protective effect (odds ratio = 0.27; 95% confident interval = 0.11-0.7). Three-allele haplotypes involving T27224C polymorphism were constructed and haplotype associations between particular haplotype combinations and various diseases identified. However, the associations were weak and the overall haplotype frequency profiles in all groups were similar. The results suggest that depression, anxiety, and comorbid depression and anxiety disorders may have related etiologies. In addition, this study suggests that the TPH1 gene might play a role in the pathogenesis of these closely related disorders.

P.2.003 Tryptophan hydroxylase gene polymorphism (A218C) in homicidal schizophrenics

Re-hospitalization after discharge for acute decompensated heart failure is a common problem. Low-socioeconomic urban patients suffer high rates of re-hospitalization and often over-utilize the emergency department (ED) for their care. We hypothesized that early consultation with a cardiologist in the ED can reduce re-hospitalization and health care costs for low-socioeconomic urban patients with acute decompensated heart failure.There were 392 patients treated at our center for acute decompensated heart failure who received standardized education and follow-up. Patients who returned to the ED received early consultation with a cardiologist; 392 patients who received usual care served as controls. Thirty- and 90-day re-hospitalization, ED re-visits, heart failure symptoms, mortality, and health care costs were recorded.Despite guideline-based education and follow-up, the rate of ED re-visits was not different between the groups. However, the rate of re-hospitalization was significantly lower in patients receiving the intervention compared with controls (odds ratio 0.592), driven by a reduction in the risk of readmission from the ED (0.56 vs 0.79, respectively). Patients receiving the intervention accumulated 14% fewer re-hospitalized days than controls and 57% lower 30-day total health care cost. Despite the reduction in health care resource consumption, mortality was unchanged. After accounting for the total cost of intervention delivery, the health care cost savings was substantially greater than the cost of intervention delivery.Early consultation with a cardiologist in the ED as an adjunct to guideline-based follow-up is associated with reduced re-hospitalization and health care cost for low-socioeconomic urban patients with acute decompensated heart failure.

P.6.026 No association between the tryptophanhydroxylase gene polymorphism and major depressive disorders and antidepressant response

P.6.026 No association between the tryptophanhydroxylase gene polymorphism and major depressive disorders and antidepressant response