S.-J. Tsai

Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder

Serotonin systems appear to play a key role in the pathogenesis of major depression and the therapeutic mechanisms of antidepressants. The firing rate of dorsal raphe serotonergic neurons is controlled by somatodendritic 5-hydroxytryptamine 1A (HTR1A) autoreceptors, and desensitization of these receptors is implicated in the antidepressant mechanism of selective serotonin reuptake inhibitors. We tested whether a functional polymorphism (C-1019G) in the promoter region of the HTR1A gene and serotonin-related genetic variants are related to fluoxetine antidepressant effect. We genotyped the HTR1A C-1019G polymorphism as well as polymorphisms in the serotonin transporter gene-linked polymorphic region (SERTPR), variable-number tandem-repeat polymorphisms in intron 2 (STin2) of the serotonin transporter gene, serotonin 2A receptor (T102C), tryptophan hydroxylase (A218C), and G-protein beta3 subunit (C825T) in 224 Chinese patients from southern Taiwan with major depression, who accepted 4-week fluoxetine treatment and therapeutic evaluation. Our results demonstrated that the HTR1A −1019C/C carriers (P=0.009) and SERTPR l/l carriers (P<0.001) showed a better response to fluoxetine, while other polymorphisms were not associated with fluoxetine therapeutic response. The major limitation of this study is the lack of a placebo control. Future prospective study with placebo control may help to predict and individualize antidepressant treatment.

Glycogen synthase kinase-3β gene is associated with antidepressant treatment response in Chinese major depressive disorder

Evidence suggests that glycogen synthase kinase-3β (GSK3B) activity is increased significantly in the brain of patients with major depressive disorders (MDD). Inhibition of GSK3B is thought to be a key feature in the therapeutic mechanism of antidepressants. To investigate whether common genetic variants in the GSK3B gene are associated with MDD and the therapeutic response to antidepressants, four polymorphisms (rs334558 (−50 T>C), rs13321783 (IVS7+9227 A>G), rs2319398 (IVS7+11660 G>T) and rs6808874 (IVS11+4251 T>A)) of the GSK3B gene were genotyped in 230 Chinese MDD patients and 415 controls. Among the MDD patients, 168 accepted selective serotonin reuptake inhibitor (SSRI) (fluoxetine or citalopram) antidepressant treatment and therapeutic evaluation for 4 weeks and 117 for 8 weeks. Significant association with MDD was not shown in the alleles and genotypes of single loci or four-locus haplotypes. However, three of the four polymorphisms investigated were significantly associated with 4-week antidepressant therapeutic effect (P=0.002–0.011). Of the four-locus haplotype analysis, the GSK3B TAGT carriers showed a poorer response to antidepressants in 4-week (P<0.0001) and 8-week (P=0.015) evaluation compared with other haplotype groups and would quite likely be the non-remitter to 8-week antidepressant treatment (P=0.006). Our findings show, for the first time, that GSK3B genetic variants play a role in the SSRI antidepressant therapeutic response and support the hypothesis that drugs regulating GSK3B activity may represent a novel treatment strategy for MDD.

Gene-gene interactions of the INSIG1 and INSIG2 in metabolic syndrome in schizophrenic patients treated with atypical antipsychotics

The use of atypical antipsychotics (AAPs) is associated with increasing the risk of the metabolic syndrome (MetS), which is an important risk factor for cardiovascular disease and diabetes. Two insulin-induced gene (INSIG) isoforms, designated INSIG-1 and INSIG-2 encode two proteins that mediate feedback control of lipid metabolism. In this genetic case–control study, we investigated whether the common variants in INSIG1 and INSIG2 genes were associated with MetS in schizophrenic patients treated with atypical antipsychctics. The study included 456 schizophrenia patients treated with clozapine (n=171), olanzapine (n=91) and risperidone (n=194), for an average of 45.5±27.6 months. The prevalence of MetS among all subjects was 22.8% (104/456). Two single-nucleotide polymorphisms (SNPs) of the INSIG1 gene and seven SNPs of the INSIG2 gene were chosen as haplotype-tagging SNPs. In single-marker-based analysis, the INSIG2 rs11123469-C homozygous genotype was found to be more frequent in the patients with MetS than those without MetS (P=0.001). In addition, haplotype analysis showed that the C-C-C haplotype of rs11123469-rs10185316- rs1559509 of the INSIG2 gene significantly increased the risk of MetS (P=0.0023). No significant associations were found between polymorphisms of INSIG1 gene and MetS, however, INSIG1 and INSIG2 interactions were found in the significant 3-locus and 4-locus gene–gene interaction models (P=0.003 and 0.012, respectively). The results suggest that the INSIG2 gene may be associated with MetS in patients treated with AAPs independently or in an interactive manner with INSIG1.

Association study of angiotensin I-converting enzyme polymorphism and symptomatology and antidepressant response in major depressive disorders.

Summary. Angiotensin-converting enzyme (ACE) inhibitor has mood-elevating effects, and central ACE activity is increased for suicidal patients. In addition, substance P (SP), which is degraded by ACE, has been implicated in the pathogenesis of, and evaluated in the treatment for, major depressive disorder (MDD). The present study has tested the hypothesis that an ACE-gene insertion/deletion (I/D) polymorphism is associated with onset age, clinical manifestations, suicide history, and/or antidepressant response for two groups of MDD patients. No significant differences were demonstrated for onset age (p = 0.520), suicide history (p = 0.823), or baseline, total and cluster scores for Hamilton Depression Rating Scale comparing the three ACE genotypes. Further, previous findings that this ACE polymorphism is associated with therapeutic antidepressant effects were not replicated. The results demonstrate that these ACE variants did not play a major role in the clinical manifestations or antidepressant response for our MDD patients.

Association study of the dopamine and serotonin transporter genetic polymorphisms and methamphetamine abuse in Chinese males

Summary. The dopamine transporter (DAT) and the serotonin transporter (5-HTT) play important roles in methamphetamine (METH) dependence because they are the target of METH action. For this study, the association between the DAT and 5-HTT polymorphisms and METH dependence were investigated for a Chinese-male sample population. The investigated polymorphisms included those of the DAT 3′-variable number tandem repeat, the 5-HTT gene promoter and a 5-HTT variable number tandem repeat polymorphisms. No significant difference was demonstrated for genotype or allele frequency, when comparing METH dependent and control cases for the DAT and the 5-HTT polymorphisms. The findings of this study suggest that these polymorphisms do not play major roles in METH dependence in the Chinese-male population.

Association study of polymorphisms in post-synaptic density protein 95 (PSD-95) with schizophrenia.

SummaryThe postsynaptic density protein 95 (PSD-95) – the prototype of this family – is a modular protein that enables anchoring of NMDA receptors, modulates NMDA receptor sensitivity to glutamate and coordinates NMDA receptor-related intracellular processes. Since hypofunction of NMDA receptors has been implicated in the pathophysiology of schizophrenia, we explored the hypothesis that genetic variants of the PSD-95 gene were associated with a diagnosis of schizophrenia. Three PSD-95 polymorphisms were studied in a sample population of 248 people with schizophrenia and 208 normal controls. One polymorphism (rs373339) was not informative in our Chinese population while the other two polymorphisms (rs2521985 and rs17203281) were analysed with chi-square tests and haplotype analysis. Results demonstrated that the two informative polymorphisms are in strong linkage disequilibrium with each other. Neither single marker nor haplotype analysis revealed an association between variants at the PSD-95 locus and schizophrenia, suggesting that it is unlikely that the PSD-95 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia in the Chinese population. Further genetic studies in schizophrenia with other PSD-95-like molecules that interact with the glutamate system are suggested.

Lack of association of catechol-O-methyltransferase gene Val108/158Met polymorphism with schizophrenia: a family-based association study in a Chinese population

Lack of association of catechol-O-methyltransferase gene Val108/158Met polymorphism with schizophrenia: a family-based association study in a Chinese population

Association analysis for genetic variants of the NMDA receptor 2b subunit (GRIN2B) and Parkinson's disease.

Summary. Recent studies have implicated N-methyl-D-aspartate (NMDA) receptor dysfunction in the pathogenesis and treatment of Parkinsons disease (PD). The NMDA receptor is composed of several subunits, of which, the receptor 2b subunit (GRIN2B) is of particular significance for PD. This subunit is found enriched in the basal ganglia, and PD-monotherapy potential has been determined for GRIN2B antagonists. For this study of a sample population consisting of 101 PD patients and 108 controls, we tested the hypothesis that an ACC ⇒ ACT transversion (2664th nucleotide of the coding sequence) affecting codon 888 (tyrosine) of GRIN2B confers susceptibility to PD, or relates to the age of onset. Comparing PD patients and controls, the distribution of the GRIN2B genotypes (p = 0.754) and alleles (p = 0.269) did not differ significantly. The onset age was not significantly different comparing the three genotypic groups (p = 0.189). Our negative findings suggest that it is unlikely that the GRIN2B C2664T polymorphism plays a substantial role in conferring susceptibility to PD in the Chinese population. Further studies with other genetic variations of NMDA subunits, relating either to PD or to the therapeutic response for PD, are suggested.

A study of alpha-adrenoceptor gene polymorphisms and Alzheimer disease.

Summary. There exists considerable evidence implicating abnormalities of the alpha (α)-adrenergic system in the development of Alzheimer disease (AD). We propose to investigate potential correlations between the presence or otherwise of α-adrenoceptor polymorphisms and the presence of AD. We studied the polymorphisms of the α1a- and the α2a-adrenoceptor genes in 142 AD patients and 98 normal controls. The result demonstrated that none of the α2a-adrenoceptor genotypes was associated with increased susceptibility to AD. However, there was a trend that the frequency of the C allele of the α1a-adrenoceptor was elevated and an excess of the CC genotype (90.1%) was found in the subjects with AD in comparison with the controls (78.6%). This association was unrelated to the apolipoprotein E genotypes. The hypothesis that the α1a-adrenoceptor gene may be implicated in the pathogenesis of AD may deserve further study.

Risk of developing Parkinson's disease among patients with asthma: a nationwide longitudinal study.

A cross‐sectional retrospective study suggested a link between allergic diseases and Parkinsons disease. However, the temporal association between asthma and Parkinsons disease remains unknown.