Dataset Information

Cell-specific effects of variants of the 68-base pair tandem repeat on prodynorphin gene promoter activity.

ABSTRACT: A polymorphic 68-bp tandem repeat has been identified within the promoter of the human prodynorphin (PDYN) gene. We found that this 68-bp repeat in the PDYN promoter occurs naturally up to five times. We studied the effect of the number of 68-bp repeats, and of a SNP (rs61761346) found within the repeat on PDYN gene promoter activity. Thirteen promoter forms, different naturally occurring combinations of repeats and the internal SNP, were cloned upstream of the luciferase reporter gene, transfected into human SK-N-SH, H69, or HEK293 cells. Cells were then stimulated with TPA or caffeine. We found cell-specific effects of the number of 68-bp repeats on the transcriptional activity of the PDYN promoter. In SK-N-SH and H69 cells, three or four repeats led to lower expression of luciferase than did one or two repeats. The opposite effect was found in HEK293 cells. The SNP also had an effect on PDYN gene expression in both SK-N-SH and H69 cells; promoter forms with the A allele had significantly higher expression than promoter forms with the G allele. These results further our understanding of the complex transcriptional regulation of the PDYN gene promoter.

SUBMITTER: Rouault M

PROVIDER: S-EPMC2995810 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Cell-specific effects of variants of the 68-base pair tandem repeat on prodynorphin gene promoter activity.

Rouault Morgane M Nielsen David A DA Ho Ann A Kreek Mary Jeanne MJ Yuferov Vadim V

Addiction biology 20100823 2

A polymorphic 68-bp tandem repeat has been identified within the promoter of the human prodynorphin (PDYN) gene. We found that this 68-bp repeat in the PDYN promoter occurs naturally up to five times. We studied the effect of the number of 68-bp repeats, and of a SNP (rs61761346) found within the repeat on PDYN gene promoter activity. Thirteen promoter forms, different naturally occurring combinations of repeats and the internal SNP, were cloned upstream of the luciferase reporter gene, transfec ...[more]

PMID: 20731629

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Project description:Cannabis use disorders (CUDs) cause substantial neuropsychiatric morbidity and comorbidity. There is evidence for gender-based differences in CUDs, for instance, a greater prevalence in males than in females. The main active component of cannabis is delta 9-tetrahydrocannabinol (delta 9-THC), a partial agonist of the cannabinoid type 1 receptor. Preclinical studies show that genetic or pharmacological manipulation of the kappa opioid receptor/dynorphin system modulates the effects of delta 9-THC.In this case-control study of adult African Americans (n=476; 206 females, 270 males), we examined the association of the functional prodynorphin 68 bp (PDYN 68 bp) promoter repeats with categorical diagnoses of cannabis dependence (Diagnostic and Statistical Manual of Mental Disorders-IV criteria), as well as with a rapid dimensional measure of maximum lifetime cannabis exposure (the Kreek-McHugh-Schluger-Kellogg cannabis scale).The PDYN 68 bp genotype (examined as short-short [SS], short-long [SL], or long-long [LL], based on the number of repeats) was not significantly associated with categorical cannabis-dependence diagnoses, either in males or in females. However, in males, the PDYN 68 bp SS+SL genotype was associated with both greater odds of any use of cannabis (p<0.05) and earlier age of first cannabis use, compared to the LL genotype (ie, 15 versus 16.5 years of age; p<0.045). Males in the SS+SL group also had greater odds of high lifetime exposure to cannabis, compared to the LL group (p<0.045). Of interest, none of the aforementioned genetic associations were significant in females.This study provides the first data on how the PDYN 68 bp genotype is associated with gender-specific patterns of exposure to cannabis. Overall, this study shows that PDYN 68 bp polymorphisms affect behaviors involved in early stages of nonmedical cannabis use and potentially lead to increasing self-exposure. These data may eventually lead to improvements in personalized medicine for the prevention and treatment of highly prevalent CUDs and neuropsychiatric comorbidities.

Dataset Information

Cell-specific effects of variants of the 68-base pair tandem repeat on prodynorphin gene promoter activity.

Publications

Cell-specific effects of variants of the 68-base pair tandem repeat on prodynorphin gene promoter activity.

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