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.

Epstein-Barr virus BZLF1 gene is activated by transforming growth factor-beta through cooperativity of Smads and c-Jun/c-Fos proteins.

Induction of Epstein-Barr virus (EBV) production in an EBV-positive cell is achieved by expression of the gene BZLF1 that switches the latent state into a lytic state. The expression of the BZLF1 gene is initiated from the promoter Zp, which is normally suppressed in EBV-transformed B cells. The BZLF1 gene can be induced for expression by activating agents, such as transforming growth factor-beta (TGF-beta) and 12-O-tetradecanoylphorbol-13-acetate. The 12-O-tetradecanoylphorbol-13-acetate-responsive element located in the Zp is the AP-1 motif. The TGF-beta-responsive element, however, has not been determined. We demonstrated that the Smad4-binding element site, GTCTG, from -233 to -229, was located in the regulatory region of the Zp relative to the BZLF1 transcription initiation site and was physically associated with Smad4. This association was important for the TGF-beta induction of Zp. We also showed from the results of co-transfection experiments and electrophoretic mobility shift assays that both the AP-1 motif and Smad4-binding element site appeared to be required for the TGF-beta-induced activation of Zp. This effect was mediated through the cooperation of Smad3/Smad4 and c-Jun/c-Fos that formed a complex. TGF-beta treatment of Rael cells induced production of infectious EBV particles that was capable of infecting EBV-negative CA46 cells and transforming normal cord blood B cells, in vitro. Those data support a mechanism that TGF-beta induces the latent EBV in cells to enter the viral lytic cycle through regulation of key viral proteins by TGF-beta signal transducers. Those findings also suggest a role of TGF-beta in EBV-associated diseases.