A functional polymorphism in the promoter region of the tryptophan hydroxylase gene is associated with alcohol dependence in one aboriginal group in Taiwan.

BACKGROUND: Polymorphisms within intron 7 of the tryptophan hydroxylase (TPH1) gene were found to be associated with alcohol dependence in different ethnic groups, including the aboriginal Bunun group in Taiwan. This study aimed to identify genetic variants at the TPH1 locus and to examine their associations with alcoholism. We hypothesized that the polymorphism of TPH1 gene is functional and influences the human circadian rhythm to contribute to the pathophysiology of alcohol dependence. METHODS: DNA from the Taiwanese Han and Bunun was subjected to sequence for screening genetic variation in the coding and promoter regions of the TPH1 locus. Polymorphisms among individuals with alcohol dependence and control subjects in two ethnic groups in Taiwan were investigated. RESULTS: Three variants in the TPH1 promoter region were identified, and the markers are in complete linkage disequilibrium in both populations. Positive associations at both allelic and genotypic levels were obtained between case and control groups in the Bunun. Expression studies demonstrated that the variants indeed affected reporter gene activity in human choriocarcinoma and colon adenocarcinoma cell lines. CONCLUSIONS: Polymorphisms in the promoter region may influence the function of the TPH1 gene and further influence the proclivity of alcohol dependence in one ethnic group in Taiwan. The associations between TPH1 genotypes and alcoholism may deserve further investigation.

Levodopa-responsive aromatic L-amino acid decarboxylase deficiency.

We report three siblings, who were treated empirically with levodopa combined with carbidopa. There was an immediate therapeutic response. Biochemical investigation surprisingly showed the clinical phenotype to be caused by aromatic L-amino acid decarboxylase deficiency. Molecular characterization showed a homozygous point mutation (c.387 G-->A) in exon 3. Kinetic studies showed the mutation to decrease the binding affinity for the substrate. This, combined with structural modeling suggesting alteration of active site configuration, provided an explanation for the therapeutic response to levodopa.

A 4-year longitudinal study on risk factors for alcoholism.

BACKGROUND: Longitudinal studies are needed to resolve inconsistencies in previous findings regarding antecedents of alcoholism. OBJECTIVE: To investigate genetic and environmental risk factors for alcoholism. DESIGN: A 4-year longitudinal cohort study. SETTING: General community. PARTICIPANTS: A population-based cohort was randomly selected from 4 aboriginal groups in Taiwan. Cohort subjects free from any alcohol use disorder at phase 1 (n=499) were reassessed approximately 4 years later (phase 2). The percentage of participants who completed the study was 98.4%. MAIN OUTCOME MEASURES: A standardized semistructured clinical interview for alcoholism and other psychiatric comorbidity was used in both phases of the study. The main outcome measure was the incidence of alcohol use disorder. Specific risk factors examined included sociodemographic factors, family history of alcoholism, extent of acculturation, psychiatric comorbidity, and alcohol-metabolizing genes. RESULTS: Using Cox proportional hazards regression analysis, the risk for alcoholism was significantly higher among subjects who were male (odds ratio [OR], 2.78; 95% confidence interval [CI], 1.79-4.32), aged 15 to 24 years (OR, 5.05; 95% CI, 2.06-6.18), unmarried (OR, 1.60; 95% CI, 1.03-2.49), and employed (OR, 2.25; 95% CI, 1.34-3.77) and had a higher educational level (OR, 1.76; 95% CI, 1.12-2.75), a family history of alcoholism (OR, 1.73; 95% CI, 1.06-2.83), and a higher extent of cultural assimilation (OR, 2.07; 95% CI, 1.28-3.35). Two specific risk pathways emerged on multivariate analysis: the highest risk was among subjects aged 25 to 34 years with anxiety disorders (OR, 16.86; 95% CI, 3.98-71.41), and the other was among men with the less active ADH2*1 gene (OR, 5.87; 95% CI, 2.73-12.60). CONCLUSION: Based on incidence cases of alcoholism among aboriginal Taiwanese, this study confirms the significant roles of anxiety disorders and of the ADH2*1 allele as antecedents of alcoholism among specific age and sex groups.

Endogenous opioid receptor genes and alcohol dependence among Taiwanese Han.

BACKGROUND: Nonselective opioid antagonists reduce alcohol consumption under various experimental situations, and several association studies have examined possible roles of opioid receptor mu (OPRM), delta (OPRD), and kappa (OPRK) genes in the development of alcohol dependence. METHODS: We examined 20 single nucleotide polymorphisms (SNPs) across the OPRM, OPRD, and OPRK genes in 158 alcohol-dependent subjects and 149 controls. Differences in allele frequency and genotype distribution between case subjects and controls, as well as the deviation from Hardy-Weinberg equilibrium, were examined using Fisher's exact tests. RESULTS: No significant difference in either allele or genotype frequency was found between case subjects and controls for each of the SNPs. CONCLUSIONS: Our findings do not support a possible role of the opioid receptor genes for the proclivity to alcohol dependence in the Taiwanese Han.

Association study of novel human serotonin 5-HT(1B) polymorphisms with alcohol dependence in Taiwanese Han.

BACKGROUND: Abnormal serotonergic pathways are implicated in numerous neuropsychiatric disorders, such as depression, anxiety, migraine, substance abuse, and alcoholism. The human serotonin receptor 1B, encoded by the HTR1B gene, is a presynaptic serotonin autoreceptor that plays a role in regulating serotonin synthesis and release. Because the linkage of antisocial alcoholism to the HTR1B gene was recently reported in two populations, it was of interest to identify genetic variants at the HTR1B locus and study their association with alcoholism in the Taiwanese Han population. METHODS: We sequenced DNA from Taiwanese Han to screen for genetic variation in the coding, promoter, and partial 3' untranslated regions of the HTR1B locus of 158 alcohol-dependent cases with withdrawal symptoms and 149 control subjects, who either never drank or drank only occasionally and in low quantities. RESULTS: Seven variants were identified. Positive associations were found between variant A-161T and alcohol dependence at both the allelic and genotypic level. In addition, an expression study showed that the A-161T variant affected reporter gene activity. CONCLUSIONS: Our results support an association between HTR1B and alcohol dependence. The HTR1B A-161T polymorphism may be valuable both as a functional and as an anonymous genetic marker for HTR1B.