Association study of tryptophan hydroxylase 2 gene polymorphisms in bipolar disorder patients with panic disorder comorbidity

Frequent comorbidity between panic disorder (PD) and mood disorders has been widely reported in clinical and epidemiological studies and, recently, an increasing attention has been paid to the cooccurrence of PD and bipolar disorder (BD). Several studies have shown that an imbalance of serotonin activity could be related to panic symptoms. Tryptophan hydroxylase 2 (TPH2) are plausible candidates for the association with PD. The aim of this study is to investigate a possible association between TPH2 gene polymorphisms and the PD comorbidity susceptibility.Our sample consisted of 515 patients; 274 patients with BD (subtypes I and II), including 45 patients with lifetime panic disorder comorbidity and 241 controls. These patients were genotyped for eight tagging single nucleotide polymorphisms of the gene of human TPH2. We found significant differences between patients with BD, with panic disorder comorbidity, and controls in the allelic analysis (rs4448731, P=0.0069; rs4565946, P=0.0359; rs4760820, P=0.0079; rs1487275, P=0.0439) and genotypic analysis (rs4448731, P=0.011; rs4760820, P=0.0259). We also identified significant differences between patients with BD, with and without panic disorder comorbidity in the allelic analysis (rs4448731, P=0.004; rs4565946, P=0.011; rs11179000, P=0.031; rs4760820, P=0.018; rs1487275, P=0.038; rs10879357, P=0.023) and genotypic analysis (rs4448731, P=0.004; rs4565946, P=0.010; rs4760820, P=0.023; rs10879357, P=0.052). The haplotype analysis in the group of patients with BD, with and without panic disorder comorbidity, was also significant (rs4448731-rs4565946, P=0.0190; rs4448731-rs4565946, P=0.0220; rs10506645-rs4760820, P=0.0360). Further studies are needed to replicate the positive association that we observed.     

Validity study of the Anxiety Symptoms Interview

The Anxiety Symptoms Interview (ASI) is a diagnostic instrument designed to identify agoraphobia (with and without panic attacks), panic disorder, social phobia, and obsessive compulsive disorder according to DSM-III criteria. The present study evaluated the diagnostic validity of this instrument by examining the extent to which ASI diagnoses assigned to 73 clinic patients agreed with diagnoses determined by clinicians. Most kappa coefficients and other concordance indicators were in the acceptable range or above, a finding that held for diagnoses overall and for specific diagnoses of agoraphobia with panic attacks, social phobia, and obsessive compulsive disorder. However, none of the 73 patients had clinician-assigned diagnoses of panic disorder (that is, without agoraphobia) or agoraphobia without panic. Limitations and applications of the ASI are discussed.     

Psychopathology of panic attacks in panic disorder

PURPOSE: This study examined the relationships among certain subtypes of panic attacks (full vs. limited symptom; spontaneous vs. situational) and between these subtypes, panic disorder subtypes, and other characteristics of panic disorder, especially agoraphobia. METHOD: Data were drawn from a large (n = 1,168) treatment study of panic disorder in which panic attacks were carefully subtyped and counted using a diary. Relationships between variables at baseline were examined primarily using non-parametric methods, and the course of improvement for panic subtypes among completers was plotted. RESULTS: The median number of spontaneous panic attacks per week at baseline was similar among patients with panic disorder without agoraphobia (PD), limited phobic avoidance (PDL), and agoraphobia (PDA). The median number of situational attacks and the median agoraphobia ratings rose progressively across diagnostic subtypes. Anticipatory anxiety, HAM-A, HAM-D, and disability scores were higher in PDA than in PD. Full and limited symptom panic attacks were positively correlated. The proportion of total attacks that were limited rose during the first two weeks of treatment, suggesting conversion of full to limited symptom attacks before complete disappearance. Spontaneous and situational attacks were correlated minimally or not at all. Agoraphobia ratings were more positively correlated with situational than with spontaneous panic attacks. Few of the correlations among measures at baseline were high. CONCLUSIONS: Full and limited symptom panic attacks differ primarily in severity. Spontaneous and situational attacks are relatively independent, and situational attacks are more closely related to agoraphobia. These findings are consistent with previous work suggesting that spontaneous attacks reflect a biological component, whereas situational attacks reflect a cognitive component in the psychopathology-- and possibly the pathogenesis-- of panic disorder. This provides a rationale for the use of combined pharmacotherapy and psychotherapy in the treatment of panic disorder. Future investigations of panic disorder should carefully separate panic attack subtypes.     

Association of polymorphisms in P2RX7 and CaMKKb with anxiety disorders

BACKGROUND: There is considerable evidence that genetic factors play an important role in the pathophysiology of affective disorders including bipolar disorder, major depressive disorder and anxiety disorders. Long-term follow up studies as well as drug treatment studies suggest that these clinical conditions share a number of pathophysiological commonalities including genetic variables. One possible candidate region is located on chromosome 12q24.31, originated from previous linkage and association studies with bipolar disorder and unipolar depression. This region contains two candidate genes for purinergic ligand-gated ion channels, P2RX7 and P2RX4, and one gene coding for calmodulin-dependent protein kinase kinase b (CaMKKb). METHODS: In the present study, we investigated the genetic associations between 15 SNPs in the candidate genes P2RX7, P2RX4 and CaMKKb on chromosome 12q24.31 in 179 patients with anxiety disorders and syndromal panic attacks versus 462 healthy controls. RESULTS: One nominal case-control association could be detected for a SNP in the 5'UTR region of P2RX4, which did not remain significant after correction for multiple testing. We found, however, a prominent association between severity of panic- and agoraphobia symptoms and an exonic SNP (rs3817190) in the CaMKKb gene and a trend for association with an exonic SNP in P2RX7 (rs1718119) with severity scores in the panic- and agoraphobia scale. CONCLUSION: The locus 12q24.31 seems to be an important genetic region for anxiety, bipolar and unipolar disorders, suggesting a genetic overlap in the group of affective disorders. The specific contribution of the herein reported gene polymorphisms to the clinical condition is still unclear and warrants further analysis.     

T-cell immunoglobulin and mucin domain 3 genetic polymorphisms are associated with rheumatoid arthritis independent of a shared epitope status

The aim of this study was to investigate T-cell immunoglobulin and mucin domain 3 (TIM3) genetic polymorphisms and rheumatoid arthritis (RA) according to the shared epitope (SE) status. Six single nucleotide polymorphisms (SNPs: rs11742259 [C/T], rs10515746 [C/A], rs35960726 [A/G], rs1036199 [A/C], rs4704846 [A/G], and rs11134551 [A/G]) in the TIM3 gene from 366 RA patients and 389 healthy controls were investigated using the real-time polymerase chain reaction method. Associations between these SNPs and clinical manifestations (including SE status) were investigated using the SPSS program and Haploview. Polymorphisms of rs35690726 (AG+ GG vs AA: 8.2% vs 1.8%, p(c) < 0.001) were significantly associated with RA with or without SE (p(c) < 0.001 or p(c) = 0.009, respectively). Polymorphisms of rs11742259 (p(c) = 0.003) and rs1036199 (p(c) = 0.012) were significantly different in RA patients with SE, but not in those without SE. In haplotype analysis with a permutation test for the first 4 SNPs (rs11742259, rs10515746, rs35690726, and, rs1036199), CCAA, CCGA, CCGC, and CAAA haplotypes were significantly associated with RA. The clinical characteristics of RA patients were not significantly associated with any TIM3 polymorphism. TIM3 genetic polymorphisms may have a role in the development of RA regardless of a shared epitope status.     

Missense mutation of the cholecystokinin B receptor gene: Lack of association with panic disorder

Cholecystokinin tetrapeptide (CCK₄) is known to induce panic attacks in patients with panic disorder at a lower dose than in normal controls. Therefore, the cholecystokinin B (CCK_B) receptor gene is a candidate gene for panic disorder. We searched for mutations in the CCK_B gene in 22 probands of panic disorder pedigrees, using single-strand conformation polymorphism (SSCP) analysis. Two polymorphisms were detected. A polymorphism in an intron (2491 C→A) between exons 4 and 5 was observed in 10 of 22 probands. A missense mutation in the extracellular loop of exon 2 (1550 G→A, Val¹²⁵→Ile) was found in only one proband. This mutation was also examined in additional 34 unrelated patients with panic disorder and 112 controls. The prevalence rate of this mutation was 8.8% in patients with panic disorder (3/34) and 4.4% in controls (5/112). The mutation did not segregate with panic disorder in two families where this could be tested. These results suggest no pathophysiological significance of this mutation in panic disorder. © 1996 Wiley-Liss, Inc.     

Exonic variants of the GABA(B) receptor gene and panic disorder

The enhancement of GABAergic neurotransmission has been closely linked to antipanic drug efficacy. This is the first study to investigate a putative association of exonic sequence variants of the human GABA(B) receptor 1 (GABA(B)R1) gene and susceptibility to panic disorder. Three DNA sequence variants in exons 1a1, 7 and 11 were assessed by polymerase chain reaction-based restriction fragment length polymorphism in a case-control study among patients with panic disorder with and without agoraphobia (DSM III-R criteria) and blood donors. There was no indication of an increased vulnerability to panic disorder or agoraphobia with respect to the allelic variants under study.     

广西人群S100B基因多态性与系统性红斑狼疮的相关性研究

目的:探讨S100B基因rs9984765、rs2839356和rs2186358遗传多态性与系统性红斑狼疮(SLE)的相关性。方法:选取313例SLE患者作为病例组,年龄和性别匹配的396例正常人作为对照组,采用单碱基延伸PCR技术(SBE-PCR)和DNA测序法对S100B基因3个位点进行基因分型检测。结果:rs9984765和rs2186358位点的基因型和等位基因频率在SLE患者组和对照组间分布差异均无统计学显著性,而rs2839356位点的C等位基因在两组间比较差异有统计学意义(P=0. 040)。进一步分析rs2839356位点的等位基因与SLE患者临床表现的关系,发现rs2839356位点的C等位基因在伴有神经系统病变的SLE患者中高于不伴有神经系统病变的SLE患者(P=0. 023)。结论:在广西人群中,S100B基因rs9984765和rs2186358位点的基因多态性可能与SLE的遗传易感性无关,而携带rs2839356的C等位基因可能具有增加SLE及其并发神经系统病变的发病风险。     

Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions*

Family and twin studies have indicated that genes influence susceptibility to panic and phobic anxiety disorders, but the location of the genes involved remains unknown. Animal models can simplify gene‐mapping efforts by overcoming problems that complicate human pedigree studies including genetic heterogeneity and high phenocopy rates. Homology between rodent and human genomes can be exploited to map human genes underlying complex traits. We used regions identified by quantitative trait locus (QTL)‐mapping of anxiety phenotypes in mice to guide a linkage analysis of a large multiplex pedigree (99 members, 75 genotyped) segregating panic disorder/agoraphobia. Two phenotypes were studied: panic disorder/agoraphobia and a phenotype (“D‐type”) designed to capture early‐onset susceptibility to anxiety disorders. A total of 99 markers across 11 chromosomal regions were typed. Parametric lod score analysis provided suggestive evidence of linkage (lod = 2.38) to a locus on chromosome 10q under a dominant model with reduced penetrance for the anxiety‐proneness (D‐type) phenotype. Nonparametric (NPL) analysis provided evidence of linkage for panic disorder/agoraphobia to a locus on chromosome 12q13 (NPL = 4.96, P = 0.006). Modest evidence of linkage by NPL analysis was also found for the D‐type phenotype to a region of chromosome 1q (peak NPL = 2.05, P = 0.035). While these linkage results are merely suggestive, this study illustrates the potential advantages of using mouse gene‐mapping results and exploring alternative phenotype definitions in linkage studies of anxiety disorder. © 2001 Wiley‐Liss, Inc.     

Association between major depressive disorder and the norepinephrine transporter polymorphisms T-182C and G1287A: A meta-analysis

Background

Previous studies have implicated norepinephrine transporter (NET) gene polymorphisms in the etiology of major depressive disorder (MDD). Recently, two single nucleotide NET polymorphisms, T-182C (rs2242446) in the promoter region and G1287A (rs5569) in exon 9, were found to be associated with MDD in different populations. However, inconsistent and inconclusive results have also been obtained.

Methods

In this study, we examined whether rs2242446 and rs5569 genetic variants are related to the etiology of MDD using a meta-analysis. Relevant case-control studies were retrieved by database searching and selected according to established inclusion criteria.

Results

Eight articles were identified that tested the relationship between the NET T-182C and/or G1287A polymorphism and MDD. Statistical analyses revealed no significant association between these polymorphisms and MDD (OR=1.23, 95% CI=0.77−1.97, P=0.38 for T-182C; OR=1.00, 95% CI=0.78−1.29, P=0.99 for G1287A).

Limitations

The results must be treated with caution because of the small sample sizes of several included studies.

Conclusions

Our findings suggest that the NET T-182C and G1287A polymorphisms are not susceptibility factors for MDD.     

The relationship between agoraphobia symptoms and panic disorder in a non-clinical sample of adolescents

BACKGROUND: The purpose of this study was to evaluate the clinical correlates of agoraphobic fear and avoidance and panic disorder in a non-clinical sample of adolescents. METHOD: In a sample of 2365 high school students, combined data from a questionnaire and a structured clinical interview were used to classify subjects with agoraphobic fear and avoidance. Panic symptoms, major depression, childhood separation anxiety disorder, anxiety sensitivity and negative affectivity were also assessed. RESULTS: Fifteen subjects met study criteria for agoraphobic fear and avoidance in the past year. Only three (20%) of those with agoraphobia symptoms reported histories of panic attacks and there was no overlap between those with agoraphobic fear and avoidance and the 12 subjects who met DSM-III-R criteria for panic disorder. However, subjects with agoraphobia symptoms and those with panic disorder reported similar levels of anxiety sensitivity and negative affectivity. Childhood separation anxiety disorder was more common among those with agoraphobic fear and avoidance compared to those without. CONCLUSION: Agoraphobic avoidance is rare in non-clinical samples of adolescents and usually not associated with panic attacks. However, adolescents with agoraphobia symptoms and those with panic disorder have similar clinical correlates consistent with a panic/agoraphobia spectrum model.     

Norepinephrine transporter polymorphisms in Tourette syndrome with and without attention deficit hyperactivity disorder: no evidence for significant association

Noradrenergic abnormalities have been proposed in the pathophysiology of Tourette syndrome and attention-deficit hyperactivity disorder. Patients with Tourette syndrome with (n=115) and without (n=110) attention-deficit hyperactivity disorder were evaluated for association with two single nucleotide polymorphisms of the norepinephrine transporter gene (SLC6A2); a T-182C single nucleotide polymorphism located in the 5' flanking promoter region and a silent mutation (G1287A) occurring in exon 9. A polymerase chain reaction restriction enzyme assay was developed for the T-182C single nucleotide polymorphism based on a prior sequencing methodology. In this case-control study, no association was identified between either polymorphism and Tourette syndrome or attention-deficit hyperactivity disorder. In a small subset, these NET polymorphisms did not predict therapeutic response to the noradrenergic transporter inhibitor atomoxetine. Further research with additional NET polymorphisms and larger sample sizes are indicated in the pursuit of biomarkers for therapeutic responders.     

Association study of tryptophan hydroxylase 2 gene polymorphisms in panic disorder

Experimental studies on serotonin (5-HT) availability suggest a role for 5-HT synthesis rate in panicogenesis. Recently, it has been discovered that the tryptophan hydroxylase gene isoform 2 (TPH2), rather than TPH1, is preferentially expressed in the neuronal tissue and, therefore, is primarily responsible for the regulation of brain 5-HT synthesis. In the present case-control genetic association study we investigated whether panic disorder (PD) phenotypes are related to two single nucleotide polymorphisms (SNP) of TPH2, rs1386494 A/G and rs1386483 C/T. The study sample consisted of 213 (163 females and 50 males) PD patients with or without affective comorbidity and 303 (212 females and 91 males) matched healthy control subjects. The allelic and genotypic analyses in the total sample did not demonstrate significant association of PD with the studied SNPs, suggesting that these polymorphisms may not play a robust role in predisposition to PD. However, an association with rs1386494 SNP was observed in the subgroup of female patients with pure PD phenotype, indicating a possible gender-specific effect of TPH2 gene variants in PD.     

Nonfearful panic disorder in chest pain patients

The prevalence of non-fearful panic disorder (panic attacks without the experience of fear) was estimated in 199 patients consecutively referred to outpatient cardiac investigation for chest pain. Fifty-nine patients met the criteria for panic disorder, and 17 patients fulfilled the criteria for non-fearful panic disorder. The patients with non-fearful panic disorder had lower scores on self-reported panic symptoms and lower frequencies of agoraphobia and comorbid axis I disorders than the patients with panic disorder and had a higher prevalence of somatic disorders than the patients without panic disorder. The patients with non-fearful panic disorder did not differ significantly from the patients with panic disorder in health-related quality of life.     

The development of agoraphobia in panic disorder: a predictable process?

BACKGROUND: Panic attacks are conceptualized to be the central feature of both panic disorder without (PDU) and with agoraphobia (PDA). As a sizeable percentage of panic patients do not develop avoidance behavior, other factors than 'panic attacks', in general, must influence the different courses of the disorder. METHOD: We studied 84 outpatients suffering from PDU or PDA concerning different factors which were hypothesized to influence the development of agoraphobia. RESULTS: 'Earlier age of onset', 'fear of losing control' and 'chills or hot flushes' turned out to correlate statistically significantly with PDA, while 'chest pain or discomfort' occurred more often in PDU. Limitations: The present study used retrospective data. CONCLUSIONS: The results of this study suggest that the development of agoraphobia in panic disorder is influenced by specific variables and is not a purely coincidental process.     

Sex differences in allelic frequencies of the 5-HT2C Cys23Ser polymorphism in psychiatric patients and healthy volunteers: findings from an association study

Polymorphisms in the serotonergic system are believed to play a role in the etiology and treatment of different psychiatric illnesses. The 5-HT2C receptor gene is X-linked, with a frequent mutation at nucleotide 68 leading to a Ser-->Cys transition at amino acid 23. Recent studies have demonstrated an impaired function of 5-HT2C receptors and an increased production of the major noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol in the cerebrospinal fluid among the subjects carrying the Ser23 allele (Lappalainen et al., 1999). Biol. Psychiatry 46:821). We genotyped patients with alcohol dependence, panic disorder without agoraphobia, generalized anxiety disorder, narcolepsy and normal healthy volunteers for the 5-HT2C Cys23Ser polymorphism. 5-HT2C Cys23Ser allele frequencies and genotypes did not differ among patients with alcohol dependence, panic disorder, generalized anxiety disorder, narcolepsy and normal healthy volunteers. In an overall analysis, female subjects (n = 173) displayed a higher frequency of 5-HT2C Ser23 alleles as compared to males (n = 298, P = 0.0178). The potential mechanisms of the observed gender difference in allele frequencies, including transmission ratio distortion, are discussed.     

Long-term outcome of panic disorder with agoraphobia treated by exposure.

BACKGROUND: There is a paucity of long-term outcome studies of panic disorder that exceed a 2-year follow-up. The aim of the study was to evaluate the long-term follow-up of patients with panic disorder with agoraphobia treated according to a standardized protocol. METHODS: A consecutive series of 200 patients satisfying the DSM-IV criteria for panic disorder with agoraphobia was treated in an out-patient clinic with behavioural methods based on exposure homework. One hundred and thirty-six patients became panic free after 12 sessions of psychotherapy and 132 were available for follow-up. A 2- to 14-year (median = 8 years) follow-up was performed. Survival analysis was employed to characterize the clinical course of patients. RESULTS: Thirty-one of the 132 patients (23%) had a relapse of panic disorder at some time during follow-up. The estimated cumulative percentage of patients remaining in remission was 93.1 after 2 years, 82.4 after 5 years, 78.8 after 7 years and 62.1 after 10 years. Such probabilities increased with younger age, and in the absence of a personality disorder, of high pre-treatment levels of depressed mood, of residual agoraphobic avoidance after exposure, and of concurrent use of benzodiazepines and antidepressant drugs. CONCLUSIONS: The findings suggest that exposure treatment can provide lasting relief to the majority of patients with panic disorder and agoraphobia. Disappearance of residual and subclinical agoraphobic avoidance, and not simply of panic attacks, should be the aim of exposure therapy.     

Agoraphobia without history of panic disorder

The purpose of this paper is to discuss the validity of the DSM‐diagnosis agoraphobia without history of panic disorder. The question posed is whether agoraphobia without history of panic disorder is a separate entity, or whether it is related to panic disorder. Research papers, including population‐based as well as clinical studies, have been reviewed. The inconclusiveness of the research together with methodological deficits do not constitute sufficient evidence to conclude that agoraphobia without history of panic disorder is a separate category. Copyright © 2001 John Wiley & Sons, Ltd.     

Treating medication-resistant panic disorder: predictors and outcome of cognitive-behavior therapy in a Brazilian public hospital

BACKGROUND: In Brazil, treatment of panic disorder is most frequently initiated with pharmacotherapy, but only half of the patients can be expected to be panic free after medication. Studies have suggested that individual or group cognitive-behavior therapy (CBT) is an effective treatment strategy for panic patients who have failed to respond to pharmacotherapy. METHODS: Thirty-two patients diagnosed with panic disorder with agoraphobia having residual symptoms despite being on an adequate dose of medication were treated with 12 weeks of group CBT. The outcome was evaluated for panic frequency and severity, generalized anxiety, and global severity. Comorbid conditions, a childhood history of anxiety, and defense mechanism styles were assessed as potential predictors of treatment response. RESULTS: Twenty-nine patients completed the 12-week protocol. Treatment was associated with significant reductions in symptom severity on all outcome measures (p < 0.001). Patients with depression had a poorer outcome of the treatment (p = 0.01) as did patients using more neurotic (p = 0.002) and immature defenses (p = 0.05). CONCLUSION: Consistent with previous reports, we found that CBT was effective for our sample of treatment-resistant patients. Among these patients, depression as well as neurotic defense style was associated with a poorer outcome. The use of CBT in Brazil for treatment-resistant and other panic patients is encouraged.     

Semaphorin-3A,semaphorin-7A gene single nucleotide polymorphisms,and systemic lupus erythematosus susceptibility

Abstract

Background: Semaphorin-3A (Sema3A) and Semaphorin-7A (Sema7A) play crucial roles in immune system by inhibiting T cell proliferation and leading to the secretion of pro-inflammatory cytokines. Increasing evidence suggest that Sema3A and Sema7A may link to the development and pathogenesis of systemic lupus erythematosus (SLE).

Objective: This study aims to evaluate the association of Sema3A, Sema7A gene single-nucleotide polymorphisms (SNPs) with susceptibility to SLE.

Methods: There were 495 SLE patients and 493 healthy controls in the study. Sema3A gene and Sema7A gene were genotyped by improved multiple ligase detection reaction (iMLDR), their plasma expression levels were detected by enzyme-linked immunosorbent assay (ELISA).

Results: No differences in genotype and allele frequencies of these SNPs were observed between SLE patients and healthy controls. However, analysing Sema3A and Sema7A SNPs with clinical manifestations of SLE indicated that, in Sema3A, the A allele frequencies of rs7804122 polymorphism was higher in patients with oral ulcers. In Sema7A, there were differences in allele frequencies of the rs2075589 and rs28362930 polymorphisms between SLE patients with haematological disorder and those without. The GG genotype and G allele frequencies of rs28362930 and the CC genotype, and C allele frequencies of rs741761 were both related to discoid rash in SLE patients. The allele frequency of G (rs28362930) was higher in SLE patients with renal disorder. There were differences in the genotype frequencies and allele frequencies of rs741761 between SLE patients with and without arthritis. No differences in plasma Sema3A and Sema7A levels were detected in SLE patients of different genotypes.

Conclusions: Sema3A and Sema7A gene polymorphisms are not related to SLE genetic susceptibility, but may link to several clinical features of SLE.