Chiao-Chicy Chen

Interaction between the Functional Polymorphisms of the Alcohol- Metabolism Genes in Protection against Alcoholism

The genes that encode the major enzymes of alcohol metabolism, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), exhibit functional polymorphism. The variant alleles ADH2*2 and ADH3*1, which encode high-activity ADH isoforms, and the ALDH2*2 allele, which encodes the low-activity form of ALDH2, protect against alcoholism in East Asians. To investigate possible interactions among these protective genes, we genotyped 340 alcoholic and 545 control Han Chinese living in Taiwan at the ADH2, ADH3, and ALDH2 loci. After the influence of ALDH2*2 was controlled for, multiple logistic regression analysis indicated that allelic variation at ADH3 exerts no significant effect on the risk of alcoholism. This can be accounted for by linkage disequlibrium between ADH3*1 and ADH2*2 ALDH2*2 homozygosity, regardless of the ADH2 genotypes, was fully protective against alcoholism; no individual showing such homozygosity was found among the alcoholics. Logistic regression analyses of the remaining six combinatorial genotypes of the polymorphic ADH2 and ALDH2 loci indicated that individuals carrying one or two copies of ADH2*2 and a single copy of ALDH2*2 had the lowest risk (ORs 0.04-0.05) for alcoholism, as compared with the ADH2*1/*1 and ALDH2*1/*1 genotype. The disease risk associated with the ADH2*2/*2-ALDH2*1/*1 genotype appeared to be about half of that associated with the ADH2*1/*2-ALDH2*1/*1 genotype. The results suggest that protection afforded by the ADH2*2 allele may be independent of that afforded by ALDH2*2.

Variant GADL1 and response to lithium therapy in bipolar I disorder.

BACKGROUNDnLithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment.nnnMETHODSnWe selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample.nnnRESULTSnTwo SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing.nnnCONCLUSIONSnGenetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).

Asthma and Suicide Mortality in Young People: A 12-Year Follow-Up Study

OBJECTIVEnMortality risk is relatively high in young people with asthma, and the risk may include causes of death other than those directly linked to respiratory disease. The authors investigated the association between asthma and suicide mortality in a large population-based cohort of young people.nnnMETHODnA total of 162,766 high school students 11 to 16 years of age living in a catchment area in Taiwan from October 1995 to June 1996 were enrolled in a study of asthma and allergy. Each student and his or her parents completed structured questionnaires. Participants were classified into three groups at baseline: current asthma (symptoms present in the past year), previous asthma (history of asthma but no symptoms in the past year), and no asthma. Participants were followed to December 2007 by record linkage to the national Death Certification System. Cox proportional hazards models were used to study the association between asthma and cause of death.nnnRESULTSnThe incidence rate of suicide mortality in participants with current asthma at baseline was more than twice that of those without asthma (11.0 compared with 4.3 per 100,000 person-years), but there was no significant difference in the incidence of natural deaths. The adjusted hazard ratio for suicide was 2.26 (95% CI=1.43-3.58) in the current asthma group and 1.76 (95% CI=0.90-3.43) in the previous asthma group. Having a greater number of asthma symptoms at baseline was associated with a higher risk of subsequent suicide. The population attributable fraction was 7.0%.nnnCONCLUSIONSnThese results highlight evidence of excess suicide mortality in young people with asthma. There is a need to improve mental health care for young people, particularly those with more severe and persistent asthma symptoms.

Genetic polymorphisms of the promoter region of dopamine D2 receptor and dopamine transporter genes and alcoholism among four aboriginal groups and Han Chinese in Taiwan.

This study aims to examine the relationship between the functional polymorphism at the promoter region of the dopamine D2 receptor (DRD2) gene (i.e. –141C Ins/ Del) and variable number of tandem repeat polymorphism at the 3′ untranslated region of the dopamine transporter (DAT) gene (SLC6A3) with alcoholism in a case–control study. The cases (n = 203) were alcohol dependents with withdrawal symptoms, and the controls (n = 213) were sex- and ethnicity-matched individuals who were screened to exclude those with alcohol problems among four aboriginal groups (Atayal, Ami, Bunun, and Paiwan) and Han Chinese in Taiwan. To control for potential confounding factors, we excluded tobacco abusers from control subjects in part of the analysis and compared the distribution of the genetic polymorphisms in alcoholics with severe medical complications versus those with less severe medical complications. There were no differences in allele and genotype frequencies of these two distinct genetic markers between alcoholics and control subjects in these five different ethnic groups. There was no significant linkage disequilibrium between the –141C polymorphism and two other DRD2 polymorphisms (TaqI A and NcoI). The results remained unchanged when cases were limited to alcoholics with more severe medical complications or when tobacco abusers were excluded from control subjects. The results suggest that both the DRD2 promoter region and the DAT gene do not play a significant role in conferring vulnerability to alcoholism.

Oxidative Status in Patients with Alcohol Dependence: A Clinical Study in Taiwan

The aim of this study is to examine the relationship between alcohol dependence and oxidative status. The biochemical parameters and antioxidants status were measured among 28 patients with alcohol dependence. Nineteen healthy persons without drinking problem were recruited as the control subjects. The activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (γ-GT), and levels of cholesterol, triglyceride (TG), and uric acid were significantly increased in the specimen of patients compared with control. Serum malondialdehyde (MDA) levels of the patients were found to be significantly increased compared with controls and decreased after abstinence. Superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities were, respectively, 86% and 37% lower in alcoholic patients. After 14 d of abstinence, SOD activity was significantly reduced by 85%, CAT by 52%, and GPX by 54%, whereas no change was found in activity of glutathione reductase (GR). The duration of alcohol dependence is significantly correlated with the levels of MDA. In addition, the activity of CAT was significantly correlated with MDA levels. The results of this study suggest that oxidative stress occurred during alcohol dependence and subsequently affected the antioxidants mechanisms.

Antipsychotic Drugs, Mood Stabilizers, and Risk of Pneumonia in Bipolar Disorder: A Nationwide Case-Control Study

OBJECTIVEnLike mood stabilizers, most second-generation antipsychotics are widely used to treat patients with bipolar disorder, yet their safety is still a concern. This study explored the association between antipsychotics and mood stabilizers and the risk of pneumonia, and it provides evidence-based information for clinical practice.nnnMETHODnIn a nationwide cohort of bipolar patients (ICD-9 codes 296.0 to 296.16, 296.4 to 296.81, and 296.89) derived from the National Health Insurance Research Database in Taiwan, who were admitted between July 1, 1998, and December 31, 2006 (N = 9,999), we identified 571 patients who developed pneumonia (ICD-9 codes 480 to 486 and 507) requiring hospitalization defined as cases. On the basis of risk-set sampling in a 1:4 ratio, 2,277 matched controls were selected from the same cohort. We used conditional logistic regression to assess the association between drug exposure and pneumonia and sensitivity analyses to validate the association.nnnRESULTSnCurrent use of several antipsychotics separately, including olanzapine (adjusted risk ratio [RR] = 2.97, P < .001), clozapine (RR = 2.59, P < .01), and haloperidol (RR = 3.68, P < .001), is associated with a dose-dependent increase in the risk of pneumonia. Interestingly, lithium has a dose-dependent protective effect from pneumonia. Among certain drug combinations, olanzapine plus carbamazepine had the highest risk (RR = 11.88, P < .01), followed by clozapine plus valproic acid (RR = 4.80, P < .001).nnnCONCLUSIONSnSeveral antipsychotics, but not mood stabilizers, were associated with the risk of pneumonia, which deserves our concern regarding patient safety. Some of the combinations of therapy resulted in synergy of risk.

Alcohol abuse and related factors in Asia

Alcohol problems are a global issue, and the nature of alcohol abuse is very complicated. The susceptibility to alcohol abuse varies greatly from one individual to another and also from one nation to another, depending on the availability of alcohol, a countrys regulation related to alcohol, a countrys cultural background, religious tradition and its economics. Alcohol dependence is also a complicated disease process. The prevalence of alcohol dependence also varies greatly from one ethnic group to another. Asia is the worlds largest and most populous continent. The natural disasters, religious conflicts as well as political disputes cause people lack of opportunity in many countries. People in this region do not consume more alcohol than the people in the rest of the world. The prevalence of alcohol dependence is not as high as is seen in other regions. In Asia, not only socio-economic factors, but also biological factors influence drinking behaviour. Findings of functional genetic polymorphism of the major alcohol metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) have led to the suggestion that this enzyme system may possibly play a diverse but critical role in alcohol dependence and in the alcohol-related disease process in the different ethnic groups. This paper reviews alcohol problems and related factors. Their management and prevention strategy are discussed.

METHOD OF FUNDAMENTAL SOLUTIONS FOR STOKES' FIRST AND SECOND PROBLEMS

This paper describes the applications of the method of fundamental solutions (MFS) as a mesh-free numerical method for the Stokes first and second problems which prevail in the semi-infinite domain with constant and oscillatory velocity at the boundary in the fluid-mechanics benchmark problems. The time-dependent fundamental solutions for the semi-infinite problems are used directly to obtain the solution as a linear combination of the unsteady fundamental solution of the diffusion operator. The proposed numerical scheme is free from the conventional Laplace transform or the finite difference scheme to deal with the time derivative term of the governing equation. By properly placing the field points and the source points at a given time level, the solution is advanced in time until steady state solutions are reached. It is not necessary to locate and specify the condition at the infinite domain such as other numerical methods. Since the present method does not need mesh discretization and nodal connectivity, the computational effort and memory storage required are minimal as compared to the domain-oriented numerical schemes. Test results obtained for the Stokes first and second problems show good comparisons with the analytical solutions. Thus the present numerical scheme has provided a promising mesh-free numerical tool to solve the unsteady semi-infinite problems with the space-time unification for the time-dependent fundamental solution.

Aldehyde dehydrogenase deficiency, flush patterns and prevalence of alcoholism: an interethnic comparison.

A study was performed to verify that the prevalence of alcohol abuse and dependence in Formosan aborigines differs from that of Taiwanese (Chinese Han people), using analysis of aldehyde dehydrogenase (ALDH) isozymes and flush patterns on randomly sampled 70 Atayal, 66 Paiwan, 61 Yami and 94 Taiwanese subjects were studied. The activity of an isomer of ALDH having a low Km (ALDH-I) in hair roots was analysed by isoelectric focusing assay. The subjective experience of flushing response after alcohol ingestion was assessed. Results showed that the rate of ALDH-I deficiency in Taiwanese (51.1%) was significantly higher than in aborigines, i.e., 6.4%, 3.9%, and 0% in Atayal, Paiwan, and Yami subjects, respectively. The percentage occurrence of ALDH-I deficiency and prevalence of alcohol dependence in Taiwanese and aborigines were negatively correlated. The predominant pattern of self-reported flush response after alcohol use among aborigines was of slow onset. The flush response to alcohol ingestion was examined in relation to aldehyde metabolizing enzyme. Since alcohol sensitivity is an important factor in the development and maintenance of the alcohol ingestion habit in humans, our results support the hypothesis that there is a biological basis in the different rates of alcohol abuse and dependence among different ethnic groups.

Search for mutations near the alternatively spliced 8-amino-acid exon in the GABAA receptor γ2 subunit gene and lack of allelic association with alcoholism among four aboriginal groups and Han Chinese in Taiwan

The alternatively spliced 8-amino-acid exon for the GABAA receptor gamma2 subunit gene (GABRC2) has been postulated to mediate behavioral actions of alcohol. A rapid search for splice-junction mutations near the 8-amino-acid exon using restriction enzymes which normally recognize sequences near or in the exon gave negative results among 217 alcoholics in four aboriginal groups (Ami, Atayal, Bunun and Paiwan) and Han Chinese in Taiwan. The role of the GABRC2 gene in alcoholism was further assessed by a comparison of allelic frequencies revealed by a NciI RFLP between case and control groups. No significant association of alcohol dependence with GABRC2 alleles was observed. These results suggest that the GABRC2 gene probably does not play an essential role in predisposition to alcoholism in the sample population.