Jung-Eun Choi

No association between dopamine D4 receptor gene -521 C/T polymorphism and tardive dyskinesia in schizophrenia

Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotics. We evaluated whether a candidate functional polymorphism of the dopamine D4 receptor (DRD4) gene is associated with drug-induced TD in 209 Korean schizophrenic patients with TD (n = 83) and without TD (n = 126) who were matched for antipsychotic drug exposure and other relevant variables. There was no significant association of the genotype and allele frequencies determined by the –521 C/T SNP of DRD4 between TD and non-TD patients. In addition, there was no significant difference in terms of total Abnormal Involuntary Movement Scale scores among the 3 genotype groups. Within the limitations imposed by the size of the clinical sample, these findings suggest that the DRD4 –521 C/T SNP does not contribute significantly to the risk for TD.

Association study between glutathione S-transferase GST-M1, GST-T1, and GST-P1 polymorphisms and tardive dyskinesia.

Data from several studies suggest that oxidative stress may play a role in the pathophysiology of tardive dyskinesia (TD). Glutathione S‐transferase (GST) enzymes play important roles in protecting cells against oxidative stress. In the present study, we investigated the hypothesis that polymorphisms in genes for these detoxifying enzymes can influence susceptibility to TD in patients with schizophrenia.

Association between Antipsychotics-Induced Restless Legs Syndrome and Tyrosine Hydroxylase Gene Polymorphism

Objective Restless legs syndrome (RLS) has been reported to be more prevalent in schizophrenic patients who take antipsychotics. The cause of RLS is unknown but associated with dopaminergic deficiency. Tyrosine hydroxylase (TH) is the enzyme responsible for catalyzing the conversion of L-tyrosine to DOPA. The purpose of this study is to determine whether the TH gene Val81Met polymorphism is associated with antipsychotic-induced RLS. Methods One hundred ninety Korean schizophrenic patients were evaluated by the diagnostic criteria of the International RLS Study Group (IRLSSG). The genotyping was performed by PCR-based methods. Results Of the one hundred ninety schizophrenic patients, 44 (23.2%) were found to have RLS. Although there were no significant associations between TH genotypes or allele frequencies and RLS, when separate analyses were performed by sex (male or female), we detected significant differences in the frequencies of the genotype (χ2=6.15, p=0.046) and allele (χ2=4.67, p=0.031) of the TH gene Val81Met polymorphism between those with and without RLS in the female patients. Conclusion These findings suggest that the TH gene Val81Met SNP might be associated with antipsychotic-induced RLS in female schizophrenic patients.

The application of an in situ karyotyping technique for mesenchymal stromal cells: a validation and comparison study with classical G-banding

The cytogenetic analysis of mesenchymal stromal cells (MSCs) is essential for verifying the safety and stability of MSCs. An in situ technique, which uses cells grown on coverslips for karyotyping and minimizes cell manipulation, is the standard protocol for the chromosome analysis of amniotic fluids. Therefore, we applied the in situ karyotyping technique in MSCs and compared the quality of metaphases and karyotyping results with classical G-banding and chromosomal abnormalities with fluorescence in situ hybridization (FISH). Human adipose- and umbilical cord-derived MSC cell lines (American Type Culture Collection PCS-500-011, PCS-500-010) were used for evaluation. The quality of metaphases was assessed by analyzing the chromosome numbers in each metaphase, the overlaps of chromosomes and the mean length of chromosome 1. FISH was performed in the interphase nuclei of MSCs for 6q, 7q and 17q abnormalities and for the enumeration of chromosomes via oligo-FISH in adipose-derived MSCs. The number of chromosomes in each metaphase was more variable in classical G-banding. The overlap of chromosomes and the mean length of chromosome 1 as observed via in situ karyotyping were comparable to those of classical G-banding (P=0.218 and 0.674, respectively). Classical G-banding and in situ karyotyping by two personnel showed normal karyotypes for both cell lines in five passages. No numerical or structural chromosomal abnormalities were found by the interphase-FISH. In situ karyotyping showed equivalent karyotype results, and the quality of the metaphases was not inferior to classical G-banding. Thus, in situ karyotyping with minimized cell manipulation and the use of less cells would be useful for karyotyping MSCs.

Lack of Association between Glutathione S-Transferase-M1, -T1, and -P1 Polymorphisms and Olanzapine-Induced Weight Gain in Korean Schizophrenic Patients.

Objective Oxidative stress may be an important pathogenic mechanism in the obesity and metabolic syndrome. The aims of this study was to assess the possible association between the oxidative stress related Glutathione S-Transferase genes (GST-M1, GST-T1, and GST-P1) variants and the olanzapine-induced weight gain in Korean schizophrenic patients. Methods We categorized 78 schizophrenic patients into two groups the more than 7% weight gain from baseline (weight gain ≥7%) and the less weight gain (weight gain <7%) groups according to weight change between before and after long-term olanzapine treatment (440±288 days). All participants were genotyped for the GST-M1, GST-T1 and GST-P1 genes. Differences in allele frequencies between cohorts with different body weight changes were evaluated by a chi-square analysis and Fishers exact test. The multifactor dimensionality reduction (MDR) approach was used to analyze gene-gene interactions. Results Mean body weight gain was 5.42 kg. There was no difference in the null genotype distribution of GST-M1 and -T1 between subjects with body weight gain ≥7% compared to subjects with body weight gain <7% (p>0.05). No significant difference in GST-P1 genotype and allele frequencies were observed between the groups (p>0.05). MDR analysis did not show a significant interaction between the three GST gene variants and susceptibility to weight gain (p>0.05). Conclusion These findings do not support a relationship between the genetic variants of three GST genes (GST-M1, -T1 and -P1) and weight gain in Korean schizophrenic patients receiving olanzapine treatment.

No Evidence for Association between Tyrosine Hydroxylase Gene Val81Met Polymorphism and Susceptibility to Tardive Dyskinesia in Schizophrenia

Objective Tyrosine hydroxylase (TH) is the rate-limiting enzyme in dopamine biosynthesis. Because the TH Val81Met polymorphism is located in the amino-terminal regulatory domain of the tetrameric enzyme, it is a candidate marker for susceptibility to dopamine-related traits. We investigated the hypothesis that TH Val81Met polymorphism can influence susceptibility to tardive dyskinesia (TD) in schizophrenia. Methods TH Val81Met polymorphism was analyzed by PCR-based methods in 83 schizophrenic patients with TD and 126 schizophrenic patients without TD, matched for antipsychotic drug exposure and other relevant variables. Results There was no significant association of the genotype and allele frequencies determined by the TH Val81Met polymorphism between TD and non-TD patients. In addition, there was no significant difference in terms of total Abnormal Involuntary Movement Scale scores among the three genotype groups. Conclusion Within the limitations imposed by the size of the clinical sample, these findings suggest that the Val81Met polymorphism of the TH gene does not contribute significantly to the risk for TD.

Dysregulation of Telomere Lengths and Telomerase Activity in Myelodysplastic Syndrome

Background Telomere shortening is thought to be involved in the pathophysiology of myeloid malignancies, but telomere lengths (TL) during interphase and metaphase in hematopoietic malignancies have not been analyzed. We aimed to assess the TLs of interphase and metaphase cells of MDS and telomerase activity (TA) and to find out prognostic significances of TL and TA. Methods The prognostic significance of TA by quantitative PCR and TL by quantitative fluorescence in situ hybridization (QFISH) of interphase nuclei and metaphase chromosome arms of bone marrow cells from patients with MDS were evaluated. Results MDS patients had shorter interphase TL than normal healthy donors (P<0.001). Average interphase and metaphase TL were inversely correlated (P=0.013, p arm; P=0.029, q arm), but there was no statistically significant correlation between TA and TL (P=0.258). The progression free survival was significantly shorter in patients with high TA, but the overall survival was not different according to average TA or interphase TL groups. Multivariable Cox analysis showed that old age, higher International Prognostic Scoring System (IPSS) subtypes, transformation to AML, no history of hematopoietic stem cell transplantation and short average interphase TL (<433 TL) as independent prognostic factors for poorer survival (P=0.003, 0.001, 0.005, 0.005, and 0.013, respectively). Conclusions The lack of correlation between age and TL, TA, and TL, and the inverse relationship between TL and TA in MDS patients reflect the dysregulation of telomere status and proliferation. As a prognostic marker for leukemia progression, TA may be considered, and since interphase TL has the advantage of automated measurement by QFISH, it may be used as a prognostic marker for survival in MDS.